regression of primarypulmonaryhypertension · tbolismcould be excluded as a cause ofher recent...

British Heart Journal, 1976, 38, 264-270.

Regression of primary pulmonary hypertension

P. D. V. Bourdillon' and C. M. OakleyFrom The Department of Medicine (Clinical Cardiology), Royal Postgraduate Medical School, HammersmithHospital, London

A girl who presented in childhood with advanced primary pulmonary hypertension and whose condition laterimproved is described. This is the first time to our knowledge that documented regression of thedisease has been reported.

Idiopathic pulmonary hypertension, including no relevant family history; the parents and a youngerchildhood and familial primary pulmonary hyper- sister were healthy.tension, is usually a fatal disease. Wood (1956) She had been apparently quite well until the age of 10reported an average survival of 3-2 years from the when in May 1966 she fainted momentarily. Betweenonset of symptoms in a series of 20 patients. A few June 1966 and December 1966 she fainted six times,patientslivmuch longer and showrelativelylong-always when running or climbing stairs. Since the onset

patients live muc longer and shwmOre ativey long- of the fainting episodes she had also noticed breathless-term stability, but even in these more fortunate ness on exertion and could not walk at a normal pace oncases eventual deterioration and death is still the the flat without dyspnoea.rule. Nielsen and Fabricius (1961) reported 3 out of The patient was first seen at Hammersmith Hospital14 patients who were still living 15 to 20 years after in April 1967 at the age of 11 years and was then over-the onset of symptoms. Charters and Baker (1970) weight (40 4 kg and 145 cm, on the 90th centile fordescribed a case of primary pulmonary hyper- weight and the 50th centile for height), but looked fit.tension in a man who died at the age of 25 years, 19 There were no signs of puberty. She was acyanotic andyears after the onset of symptoms. In their huge not clubbed. The heart rate and rhythm were normal;

the blood pressure was 105/75 mmHg (14 0/100 kPa)series Wagenvoort and Wagenvoort (1970) recordeda u h a in fsvr umnr yetnin4 ouof ainsi hm yposhdbe

but she had signs of severe pulmonary hypertension.4 out of 10pabtents in wnom symptoms had been The jugular venous pressure showed a 6-cm 'a' wave.present for between 20 and 29 years before death. There was a pronounced right ventricular heave andWe report here a patient in whom primary pul- pulmonary arterial pulsation with a palpable pulmonary

monary hypertension regressed after the disorder component of the second sound. There was a right ven-had reached an advanced stage. We have been un- tricular fourth sound, a pulmonary ejection click, and aable to find any reports of comparable cases. The soft, short, ejection systolic murmur. The pulmonaryonly other report of improvement was of a patient component of the second sound moved normally withwhose pulmonary hypertension was thought to be respiration and there was no pulmonary regurgitantthromboembol.cin origin (Wilcken, MacKenzie, murmur. The lung fields were clear on auscultation.

and Goodwin, 1960): these authors recorded a dropin pulmonary artery pressure from 65/28 to 40/20mm Hg (8.6/3.7 to 5 3/2 7 kPa) during anticoagulant IHnvestigateonstreatment. Haematological and biochemical investigations were all

normal. The electroencephalogram showed somegeneralized disorganization but no localizing features.

Case report The electrocardiogram showed severe right ventricularhypertrophy with widespread T wave changes (Fig. 1).

The patient was born at term after a normal pregnancy The chest radiograph showed slight cardiac enlargementand uncomplicated delivery. Her development was with prominent main pulmonary arteries and clear lungnormal and she had had no serious illnesses. There was fields with normal or reduced vascularity (Fig. 2a).

Cardiac catheterization had already been carried out

Received 29 September 1975. elsewhere in January 1967. The results (see Table)'Present address: Wessex Cardiothoracic Centre, Western confirmed that she had severe pulmonary hypertensionHospital, Oakley Road, Shirley, Southampton. without any evidence of structural heart disease.

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Regression of primary pulmonary hypertension 265

25J.1b corded at this time are shown in Fig. 3A. The electro-cardiogram was unchanged from 1967. Chest x-rayexamination, however, showed a further increase inheart size. A perfusion lung scan was within normal

Ir III aVR aVL oVF limits. Right heart catheterization was repeated (Table).A A pulmonary angiogram showed normal peripheralD pulmonary arteries but dilatation of the main pulmonary

arteries. It was thought that pulmonary thromboem-Tbolism could be excluded as a cause of her recent de-

terioration. She was, however, continued on anticoagu-lants and put on an 800-calorie diet.The patient continued to have syncopal episodes in

VI Y2 V3 V4 V5 Vb 1970 and 1971 and had to limit her activities evenfurther. The early diastolic murmur in the pulmonary

1.11.73 area became louder. Then, inexplicably, the slow de-terioration was halted and she gradually improved. Herlast syncopal episode was in 1971. In retrospect wethink that the improvement probably started in 1972,III. when she was 16. Subjective improvement was first

B I II II 88I[aS -:GVR L aFnoted at her clinic visit in September 1972. Disap--_ pearance of the pulmonary regurgitant murmur and lossof ejection click were noted in May 1973.

In 1973 she left school, and her father bought her acar because of her disability. She learned to drive and

XwOwmdrove to and from a sedentary job as a clerk with a travel

Y--VVW:-:-:= By 1975 she had become virtually asymptomaticand now leads a normal, active life. She was readmitted

8.5.75 to Hammersmith Hospital for reinvestigation. At 19 she..- was a fit-looking, well-developed young woman, still

E..- slightly obese. The cardiac findings were totally changed.i_ -.- _*The giant venous 'a' wave in the neck, the pulmonaryaVL i.. ejection click, and the murmur of pulmonary regurgita-

c 1 I III aVR aFLG'S tion had all disappeared. The right ventricular heaveand the palpable pulmonary closure sound were less

-. - - prominent. The phonocardiogram (Fig. 3B) showed onlya soft systolic murmur, with a prominent pulmonary

_component of the second sound, but no ejection click orVI Y2 V3 Y4 VS Vb early diastolic murmur. The electrocardiogram hadFIG. 1 Conparison of(A) electrocardiograms recorded changed considerably, with reduction in voltage of the

R waves in the right praecordial leads and improvementin 1968 (when agedllyears), (B) 1973 (aged 17), and in the previously widespread, steeply inverted T waves(C) 1975 (aged 19), suggests decrease in severity of (Fig. 1). The chest x-ray picture had changed. Theright ventricular hypertrophy between 1973 and 1975. steadily enlarging heart seen in films taken between(Electrocardiograms all recorded at normal stan- 1967 and 1971 (Fig. 2) was reduced to normal size.dardization, i.e. 10 mm= 1 mV.) Cardiac catheterization was repeated (Table). The

pulmonary angiogram was unchanged and still showeddilated main pulmonary arteries with normal peripheral

The diagnosis of primary pulmonary hypertension arteries without obstruction. Ventilation and perfusionwas accepted and treatment with oral anticoagulants was lung scans showed no significant abnormality. Thestarted. echocardiogram showed that the movement of the

interventricular septum was normal.ProgressFrom 1967 to 1969 the patient continued to be breathless Haemodynamic data (Table)and feel faint on exertion. She was readmitted toHammersmith Hospital in August 1969 because of Between 1967 and 1969 the pulmonary arterial pressuregradual deterioration after a synoopal attack in July 1969 was recorded three times and was at or near systemicand considerable decrease in exercise tolerance. Physical level at rest on each occasion. Because of her parlousfindings were similar to those in 1967 except that she was state and the possible risks involved no exercise testseven more obese and an early diastolic murmur in were performed. There was no fall in the pulmonarythe pulmonary area had appeared. Phonocardiograms re- arterial pressure with administration of 100 per cent



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266 Bourdillon and Oakley

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FIG. 2 Chest x-rays taken in 1967, 1970, 1971, and 1975 show a progressive increase in heartsizefrom 1967 to 1971 (Fig. A, B, C) with a pronounced decrease in D.

oxygen. Bicycle ergometry mn 1969 showed that her mng severe state of primary pulmonary hypertensionwork load was only 200 kpm/mnute She was raises a number of points worthy of discussion,

then stopped by dyspnoea with a pulse rate of 150/m particularly in relation to the possible causes or theThe transseptal left heart catheterization carried out in mechanism of raised pulmonary vascular resistance.1967 excluded any abnormality in the left heart chambers The diagnosis of primary pulmonary hyper-or septal defect. ..At her fourth study in 1975 the pulmonary artery tauension is lmaeonlry aftertexlsion-ofidnpatifilablepressure had fallen to just above normal with a normalcassopumnrhyetsi-npriul,

systemic pressure and the previously very reduced postcapillary pulmonary hypertension caused bycardiac output had risen to low normal limits. Bicycle mitral valve disease or left heart failure, and pre-ergometry showed that her exercis'e performance was capillary pulmonary hypertension caused by con-now within normal limits (Fig. 4). Lung function is now genital septal defects with the Eisenmenger reaction.normal apart from low CO transfer which is 19-3 (pre- Pulmonary thromboembolism or primary lungdicted 25-7 to 32-9 ml/min per mmHg) consistent with a disease also need to be eliminated. In our patientslight loss of pulmonary vascular bedThe evidence of true regression of her pulmonary orasnic heviecfpiart undisease.hdeePecuded ondahrevascular disease was considered to be irrefutable, wasomnoevidence ofpiary lundhoeisease pusblmonaythough it was too early to conclude that she was 'normal'trmomoim wsathoeia osblt

as 'cured'. but was most unlikely in a girl of 11, and wasexcluded by the normal pulmonary angiogram and

Discussion lung scan in 1969 (Wilson et al., 1973). The lack ofrespiratory illness or haemoptyses, repeatedly

This case of apparent improvement from a present- clear lung fields on x-ray examinatiQn, and normal

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TABLE Cardiac catheterization data recorded in 1967 (2 procedures), 1969 and 1975

SVC IVC RA RV PA PV LA LV SA SA CI TPR(100% 02)

1967 (a)Pressures (mmHg) - - M 7'5 - 76/40 - - - 100/7002 saturation (%) 74 71 68 67 67 - - - 89 99

1967 (b)Pressures (mmHg) - - M 5 96/8 100/60 M 7 106/8 120/75 -

M 8002 saturation (%) - - 62 90 94 93 87

1969 1-5 17-0Pressures (mmHg) - M 10 95/12 95/39 - - - 100/70*

M 5802 saturation (%) - - - 64 - - - 97 -

1975 2-3 3-8Pressures (mmHg) - M 2 40/4 40/14 - - - 110170 -

M 2402 saturation(%) - - - 66 - - - 97

*Sphygmomanometer cuff measurement. RA=right atrium; RV=right ventricle; PA=pulmonary artery; SA=systemicartery; LA=left atrium; LV=left ventricle; IVC=inferior vena cava; SVC=superior vena cava; PV=pulmonary vein;M=mean; 100% 02 indicates administation of 100% 02 at time of sampling; CI=cardiac index in 1/min per M2; TPR=totalpulmonary resistance in units/m2.Conversion from Traditional units to SI units: 1 mmHgp 0 133 kPa.

0lung scans made pulmonary venous obstruction (as (1960), Roberts (1963), and Wagenvoort andin pulmonary veno-occlusive disease) extremely Wagenvoort (1970) showed that in most patientsunlikely in our patient. (including children) the pulmonary hypertension

It is unlikely that the anticoagulants were directly was not apparently present from birth but wasrelevant to the patient's recovery or that the associa- acquired. Subramanian et al. (1974) found thetion between treatment and improvement points to 'adult' pattern offragmented elastic fibres in the walla thromboembolic origin of the pulmonary hyper- of the main pulmonary arteries in all of their 11tension. It was hoped that anticoagulation would cases. This observation indicated that the diseaseprevent pulmonary arterial thrombosis of throm- had been acquired after a postnatal and childhoodboembolism as a secondary complication of the interval of low pulmonary artery pressure even inadvanced stages of the disorder and that it might, the 6 of their patients who died before the age of 16.therefore, prolong life (Wagenvoort and Wagen- A family predisposition to the development of thevoort, 1970). This is disputed by Walcott, Burchell, disease in childhood sheds no light on aetiology, butand Brown (1970) who noted in a retrospective these cases sometimes survive for a relatively longstudy of 23 patients with primary pulmonary time (Fleming, 1960; Melmon and Braunwald,hypertension that anticoagulation did not appear 1963). Wagenvoort and Wagenvoort (1970) des-to alter the natural history of the disease or the cribed 11 such familial cases and from the pub-survival time. In the absence of specific therapy lished reports collected 47 other cases from 20for this disease of undetermined aetiology, however, different families. There was no family historywe believe that oral anticoagulants should be pre- associated with our patient.scribed in idiopathic pulmonary hypertension and Farrar (1963) and Wade and Atukorale (1975)continued indefinitely. have contended that the disease is part of an auto-

Primary pulmonary hypertension is commonest immune process. This is supported by the associa-in young women-usually in those who have been tion of pulmonary hypertension with rheumatoidpregnant. In childhood, girls and boys are equally and other collagen diseases as well as with Raynaud'saffected; the disorder is sometimes familial, and it phenomenon as described by Walcott et al. (1970)may occur in sibs. The nature of the underlying and by Wagenvoort and Wagenvoort (1970). Bothdisease process is still undetermined. Though a of Trell's cases (1973) of primary pulmonarycongenital abnormality in the pulmonary arterial hypertension with an unusually long duration hadwall remains a possibility, Heath and Edwards Raynaud's phenomenon. There was no evidence of



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INSPIRATION EXPIRATION

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PAA

MA ~#i

BPAmh J -

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FIG. 3 Phonocardiograms recorded in 1969 (A) show loud pulmonary component of secondsound which moves normally with respiration, and an ejection click (arrowed). Early diastolicmurmur, then clinically prominent, does not show clearly. Phonocardiogram in 1975 (B) showsonly soft systolic murmur. The ejection click has gone. The pulmonary component of secondsound still appears to be loud. MA=mitral area. PA =pulmonary area.

collagen vascular disease in the patient described coats of arteries react to a stretching force by con-here. Farrar also noted that in some cases the onset striction. Wood (1959) found that patients withof the disease seemed to be preceded by a virus-like primary pulmonary hypertension responded toillness, and this association was also mentioned by injection of acetylcholine into the pulmonary arteryWalcott and his colleagues (1970). Again there was by a brisk fall in pulmonary artery pressure, and thisno history of such an illness in our patient before the seemed to support the concept of vasoconstriction.onset of her symptoms. The pathological work of Wagenvoort and Wagen-The use of the anorectic drug aminorex fumarate voort (1970) led them to support a vasoconstrictive

(Menocil) has been implicated in some cases of pul- pathogenesis and to reintroduce Wood's termmonary hypertension but there was no history of 'vasoconstrictive pulmonary hypertension' to des-the use of this drug or of other 'slimming' drugs in cribe this group with primary pulmonary hyper-our patient whose disease started some years before tension. The notion that there exists an individualshe had any interest in slimming. susceptibility or hyperreactivity of the muscularWood (1952) was probably the first to suggest that pulmonary arterioles in patients who develop

pulmonary hypertension might be vasoconstrictive pulmonary hypertension in response to the variousin origin and a self-perpetuating response to some stimuli that may trigger pulmonary vasoconstrictioninitiating degree of pulmonary hypertension itself. is all that is known about causation. Such stimuliEvans, Short, and Bedford (1957), and Wade and may include a high pulmonary artery pressure andBall (1957) supported this view and Short (1959) pulse pressure associated with intracardiac shunts,cited earlier physiological work which showed that, increased flow, polycythaemia, hypoxia, and pos-like smooth muscle in other situations, the vascular sibly also sexual maturation in the female and



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avoid pregnancy has been upheld, we no longer feel180 justified in recommending sterilization. The case is

without parallel in our experience, but provided her160 improvement is maintained over the next few years

0-t __ _ I then it may even be reasonable for her to consider/140 ° pregnancy, though we feel uneasy about the risk of/ '* / - pregnancy then provoking a recrudescence of her/ // -120 X disease.

80- -106 80 References

6o0 / 80 Charters, A. D., and Baker, W. de C. (1970). Primary pulmo-

/- nary hypertension of unusually long duration. British60 Heart_Journal, 32, 130.Evans, W., Short, D. S., and Bedford, D. E. (1957). Solitary

pulmonary hypertension. British Heart Journal, 19, 93.20- Farrar, J. F. (1963). Idiopathic pulmonary hypertension.

American Heart J'ournal, 68, 128.Fleming, H. (1960). Primary pulmonary hypertension in

0 I 2 eight patients including a mother and her daughter.0 0.SIk 0 bS2S0 Australasian Annals of Medicine, 9, 18.

Grover, R. F., Vogel, J. H. K., Voigt, G. C., and Blount, S. G.FIG. 4 Result of progressive exercise test in 1975. (1966). Reversal of high altitude pulmonary hypertension.Increments in heart rate (above) and ventilation American J'ournal of Cardiology, 18, 928.(below) fell within expected normal range (fine Heath, D., and Edwards, J. E. (1960). Configuration of elasticlines) for increase in oxygen uptake achieved. tissue of pulmonary trunk in idiopathic pulmonaryhypertension. Circulation, 21, 59.

Melmon, K. L., and Braunwald, E. (1963). Familial pul-monary hypertension. New England Jrournal of Medicine,

pregnancy. Reversal of such a postulated vicious 269, 770.spiral could possibly explain the recovery in our ...Nielsen., N. C., and Fabricius, J. (1961). Primary pulmonarypatient.r y hypertension with special reference to prognosis. ActaPatient. Medica Scandinavica, 170, 731.A higher pulmonary artery pressure than normal Roberts, W. C. (1963). The histologic structure of the

is found in most dwellers at high altitude than in pulmonary trunk in patients with 'primary' pulmonarythose who live at sea level. This is normally asymp- hypertension. American Heart J7ournal, 65, 230.tomatic and benign (Grover et al., 1966). The same Short, D. S. (1959). The application of arteriography to theauthors described the reversal of unusually severe pathological study of pulmonary hypertension. In Pul-asymptomatic pulmonary hypertension in a patient monary Circulation, p. 240. Ed. by W. R. Adams and I.who had lived at high altitude but moved to sea Veith. Grune and Stratton, New York.level, and attributed this to relief from the hypoxic Subramanian, N., Bathviziam, A., Sukumar, I. P., Krish-stimulustopumoarvscosnaswami, S., and Cherian G. (1974). Primary pulmonarystimulus to pulmonary vasoconstriction that had hypertension. A clinicopathological study of 11 cases.

been present at altitude. It may be of significance Indian Heart Journal, 26, Suppl., p. 171.that the apparent deterioration in our patient's Trell, E. (1973). Benign idiopathic pulmonary hypertension.condition in 1969 occurred after a visit to Switzer- Acta Medica Scandinavica, 193, 137.land. Wade, G., and Atukorale, D. (1975). Observations on theThe later symptomatic and objective improve- aetiology of unexplained or primary pulmonary hyper-

ment described coincided with a late menarche at tension (abstract). British Heart Journal, 37, 550.the age of 15. This is surprising in the light of the Wade, G., and Ball, J. (1957). Unexplained pulmonary hyper-prvlneof idiopathic pulmonary hypertension tension. Quarterly Journal of Medicine, 26, 83.prevalence of- idiopathic pulmonary hypertension Wagenvoort, C. A., and Wagenvoort, N. (1970). Primary

in adult women and of its relatively common oc- pulmonary hypertension. A pathologic study of the lungcurrence after pregnancy in contrast to the relative vessels in 156 clinically diagnosed cases. Circulation, 42,rarity and equal sex ratio in children. 1163.

Pregnancy is a serious hazard in pulmonary Walcott, G., Burchell, H. B., and Brown, A. L. (1970).hypertension. These patients are advised to avoid Primary pulmonary hypertension. American Journal ofhpertegnsin.yadiisorpatctocryotubl Medicine, 493, 70.pregnancy and it is our practice to carry out tubal Wilcken, D. E. L., MacKenzie, K. M., and Goodwin, J. F.ligation. Though tubal ligation had originally been (1960). Anticoagulant treatment of obliterative pulmonaryplanned for our patient and the original advice to hypertension. Lancet, 2, 781.



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Wilson, A. G., Harris, C. N., Lavender, J. P., and Oakley, Wood, P. (1959). The vasoconstrictive factor in pulmonaryC. N. (1973). Perfusion lung scanning in obliterative hypertension. In Pulmonary Circulation, p. 297. Ed. bypulmonary hypertension. British Heart J'ournal, 35, 917. W. R. Adams and I. Veith. Grune and Stratton, New York.

Wood, P. (1952). Pulmonary hypertension. British MedicalBulletin, 8, 348.

Wood, P. (1956). Primary pulmonary hypertension. In Requests for reprints to Dr. C. M. Oakley, RoyalDiseases of the Heart and Circulation, 2nd ed., p. 83. Postgraduate Medical School, Hammersmith Hospital,Eyre and Spottiswoode, London. London W12 OHS.



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