Tobis et al. June. 1983

American Heart Journal

3 1

4.

5.

6.

7.

8.

Houk TL, Kruger RA, Mistretta CA, Riederer SJ, Shaw C-G, Lancaster JC, Flemming DC: Real-time digital K-edge sub- traction fluoroscopy. Invest Radio1 14:270, 1979. Ergun DL, Mistretta CA, Kruger RA, Riederer SJ, Chaw CG, Carbone DP: A hybrid computerized fluoroscopy technique for noninvasive cardiovascular imaging. Radiology 132:739, 1979. Kruger RA, Mistretta CA, Houk TL, Riederer SJ, Shaw CG, Goodsitt MM, Crummy AB, Swiebel W, Lancaster JC, Rowe CG, Flemming D: Computerized fluoroscopy in real time for noninvasive visualization of the cardiovascular system. Radi- ology 130:49, 1979. Strother CM, Sackett JF, Crummy AB, Lilleas FG, Zwiebel WJ, Turnipseed WD, Javid M, Mistretta CA, Kruger RA, Ergun DL, Shaw CG: Clinical applications of computerized fluoroscopy. Radiology 136:781, 1980. Nalcioglu 0, Seibert JA, Roeck WW, Friedenberg RM, Rosenberg H, Pearce JG, Gehrich JL: Evaluation of renal function by digital subtraction imaging. Sot Photo-optical Instrum Engineers 273:1, 1981. Kruger RA, Mistretta CA, Houk TL, Kubal W, Riederer SJ, Ergun DL, Shaw CG, Lancaster JC, Rowe GG: Computerized

9.

10.

11.

12.

13.

fluoroscopy techniques for intravenous study of cardiac chamber dynamics. Invest Radio1 14:279, 1979. Tobis J, Nalcioglu 0, Johnston WD, Seibert A, lseri LT. Roeck W, Elkayam U, Henry WL: Left ventricular imaging with digital subtraction angiography using intravenous injec- tion and fluoroscopic exposure levels. AM HEART .I 104:20, 1982. Ovitt TM, Cristenson PC, Fisher HD, Frost MM, Nudelman S, Roehrig H, Seeley G: Intravenous angiography using digital video subtraction: X-ray imaging system. AdNR 1:387, 1980. Sandler H, Dodge HT: The use of single-plane angiocardio- grams for the calculation of left ventricular volume in man. AM HEART J 73:325, 1968. Kennedy JW, Trenholme SE, Kasser IS: Left ventricular volume and mass from single-plane cineangiocardiogram. A comparison of anteroposterior and right anterior oblique methods. AM HEART J 60:343, 1970. Sasayama S, Nonogi H, Kawai C, Fujita M, Eiho S, Kuwaha- ra M: Automated method for left ventricular volume mea- surement by cineventriculography with minimal doses of contrast medium. Am J Cardiol 46:746, 1981.

Pulmonary hypertenebn in i atrial septai defect: High f

swu*fYl cy in young

patients

Out of 709 consecutive patients with isolated secundum atrial septal defect, the pulmonary artery systolic pressure was >50 mm Hg in 118 patients (17%). Pulmonary hypertension was present in 13% of patients under 10 years and in 14% aged 11 to 20 years. The Eisenmenger reaction was present in 9% of the 709 patients. The frequency of the Eisenmenger reaction was high in young patients and was not significantly different in pattents in the first and second decades as compared to older patients. None of our patients with pulmonary hypertension resided at high altitude. The high frequency of pulmonary hypertension in our young patients cannot be satisfactorily explained. Autopsy studies suggest that in some, pulmonary hypertension is due to the persistence of the fetal pulmonary vascular pattern. (AM HEART J 105952, 1983.)

George Cherian, D.M. (Card)., C. Babu Uthaman, D.M. (Card)., M. Durairaj, D.M. (Card)., I. P. Sukumar, D.M. (Card)., S. Krishnaswami, D.M. (Card)., P. S. Jairaj, F.R.A.C.S., S. John, M.S. (Thorac)., H. Krishnaswami, M.D. (Path)., and A. Bhaktaviziam, M.D. (Path). Vellore, India

From the Departments of Cardiology, Cardiac Surgery, and Pathology, There are variations in the natural history of certain Christian Medical College Hospital. cardiac conditions which cannot be easily explained, Received for publication Jan. 6, 1981; revision received Jan. 25, 1982; and our observations show that unlike other reports, accepted Feb. 18, 1982. pulmonary hypertension is common in our young

Reprint requests: George Cherian, D.M. (Card)., Professor of Cardiology, patients with isolated secundum atrial septal defect.

Chest Hospital, P.O. Box 4082, &fat, Kuwait. Pulmonary hypertension (PH) as a result of pulmo-

952

Volume 105

Number 6 Prevalence of pulmonary hypertension in ASD 953

nary vascular disease is the most important compli- cation that alters the natural history of secundum atrial septal defect (ASD), and it is not possible to predict the development of severe pulmonary vascu- lar disease.‘e4 PH also raises the surgical mortality of an otherwise easily and safely correctable malforma- tion.5-8 Even after surgery, the regression of PH, although common, is not always uniform or com- plete.6-g

Table I. Age distribution*

The different reports vary in the criteria used for a definition d significant PH. They have ranged from a systolic pulmonary artery (PA) pressure of 40 mm Hg to 60 mm Hg. 3v 6, *-ll The frequency of PH in isolated secundum ASD has been difficult to assess since some series include other types of atrial septal defects and associated conditions like mitral valve disease which could contribute to the PH.3s l2 Others deal with surgicaP8 or mixed surgical and nonsurgi- cal patients,3* 4, ‘* and the different age groups are not often separated. - 3 5* l2 We present here the hemody- namic data of 709 patients with isolated secundum ASD to bring out the problem of PH.

Age group Iv) SPAP > 32 mm Hg

O-10 71/175 (40%) 11-20 96/248 (39% ) 21-30 831177 (47 % ) 31-40 41/81 (50%) Above 40 16/28 (57%)

SPAP = systolic pulmonary artery pressure (mm Hg). *No. of cases = 709. Systolic PA pressure >32 mm Hg = 307 (43.3:~ ).

Table II. Frequency of pulmonary vascular resistance 25 units

Age group b-1 n %

O-10 211175 12 11-20 241248 10 21-30 301177 17 31-40 15181 19 Above 40 3128 11 All age groups 931709 13.1

p < 0.05.

METHODS RESULTS Patients studied. We reviewed the hemodynamic data

of 709 consecutive patients with isolated secundum ASD admitted to the cardiology department of the Christian Medical College Hospital, Vellore, India. None gave a history of residence at high altitude. All patients under- went routine cardiac catheterization, and left heart studies were carried out in all patients in whom there was a clinical suspicion of associated mitral valve disease or an abnormal axis on the ECG and also in some of the others as a part of the routine study. The diagnosis of isolated secundum ASD was confirmed in all these cases and those with associated lesions have been excluded. The presence of a shunt at the atria1 level was confirmed by oxymetry and/or indicator dilution curves. Some had selective pul- monary vein angiography and surgery was performed in 31 out of the 118 patients with significant PH. Autopsies were performed on four patients with significant PH. Cardiac output was calculated by means of the Fick principle. Pulmonary vascular resistance was calculated from the formula of PA mean pressure/pulmonary flow and expressed as units (units X 80 would express this as dynes . set . cm+). Since the oxygen consumption values were assumed, the calculated resistance should be inter- preted in this context. The effect of oxygen administration on the PA pressure was not studied.

Frequency of PH. out of the ‘709 patients, 307 (43.3 % ) had a systolic PA pressure exceeding 32 mm Hg. A higher proportion of patients in the third decade and above had a raised PA pressure as compared to patients in the first and second decades 03 < 0.01) (Table I). Out of these 307 patients, significant PH was present in 118 (38%) with a systolic PA pressure exceeding 50 mm Hg and 76/118 had a pressure exceeding 71 mm Hg. Signifi- cant PH while present in the first two decades was found more often in older patients (p < 0.01).

Pulmonary vascular resistance and flow. Table II shows that a pulmonary vascular resistance over 5 units, while present in 12% of patients in the first decade and in 10% in the second decade, was seen more often in older patients 0, < 0.05). The pulmo- nary vascular resistance was above 5 units in 78.8% of the patients with significant PH. The ratio of pulmonary-to-systemic flow was less than 2: 1 in the majority (70%) of patients with significant PH, and between 2-3 : 1 in 16% and over 3 : 1 in 14%.

Definition of PH. While our normal values are below 25 mm Hg, PH was defined as a peak PA systolic pressure of 32 mm Hg or more,13 and “significant” PH was considered to be present with a PA systolic pressure >50 mm Hg.3x6f7 The Eisenmenger reaction was defined as development of PH with a reversed or bidirectional shunt between the pulmonary and systemic ci.rculations at the atrial level.2

Eisenmenger reaction. Table III shows that the Eisenmenger reaction with shunt reversal was

present in 61 out of the 709 patients (9 % ). This was present even in 7% of those in the first decade and in 8% in the second decade, and surprisingly there was no significant difference between the various age groups. Of the 61 patients with the Eisenmenger reaction, 12 (20%) were in the first decade, 19 (31%)

954 Cherian et al. June, 1993

American Heart Journal

Table III. Frequency of Eisenmenger reaction

Age group n ‘Ib

All age groups First decade Second decade Third decade Fourth decade and beyond

611709 9 po 121175 7°C’ 191248 8 r,, 171177 101’0 13/109 11 !‘C,

p=NS.

in the second decade, 17 (28%) in the third decade, and the rest (21% ) were in the fourth decade or older. There was no significant difference between the various decades (p = NS) indicating that the Eisenmenger reaction was as common in the youn- ger as in the older patients. Table IV is a compara- tive study of the Eisenmenger reaction in ASD from some of the other reports23 3* 14-17

Comparative frequency of PH and PA media at autop- sy. Table V is a comparative study of the incidence of PH from some of the other series.5p 18, I9 Significant PH was present more often in our patients as compared to those in other series. Table VI shows the type of media in the pulmonary artery (fetal, adult, or transitional type) in four patients, three of whom died after surgical correction.

Follow-up after surgery. Out of the 118 patients with significant PH, 31 underwent surgical correc- tion and out of these, three patients died (mortality rate 10% ) with features of a low cardiac output. Nineteen of 28 (68%) have been followed up after surgery for an average period of 4 years. Eighteen of 19 patients were asymptomatic on follow-up and one who was in congestive cardiac failure had improved. The ejection systolic murmur disappeared in 75%, but the murmur of pulmonary regurgitation which was present preoperatively in two cases persisted. There was an average reduction of 6.6 mm in R’ in lead V1 in 85 % . Postoperative cardiac catheteriza- tion was carried out in three patients. The PA pressure decreased from 58/18 to 25110, from 96136 to 42f24, and from 71123 to 2018 mm Hg. The pulmonary vascular resistance changed from 1.13 to 3.2, from 4.9 to 5.9, and from 6.5 to 2 units, respectively.

DISCUSSION

Natural history and pulmonary vascular disease. Campbell et al.’ studied the natural history of atria1 septal defect in 100 patients; the average age at death was 39 years. PH with shunt reversal was present in 11 of their patients. Dalen et al.4 followed up 43 patients who did not have surgery for periods

Table IV. Comparative frequency of Eisenmenger reac- tion

Authors Age group Associated

(s’r) lesions

Bedford et aLI Besterman’ MarkI Gault et al.lb Wood* Young and Mark” Present series Present series Present series

10 6

10 13 6 8 9 6.8

10.5 -_.

All age groups All age groups >17 >40

All age groups >20 All age groups <IO >20

.--~

Yes Yes Yes Yes No No No No No

--..--

ranging from 20 to 30 years and found that survival was influenced mainly by pulmonary vascular dis- ease and that it was not possible to predict the development of severe pulmonary vascular disease.

Definition and type of PH. There has been no uniform definition for “significant” PH in ASD. Some reports have selected a systolic PA pressure of 40 mm Hg’O and others 60 mm Hg.Srg In the majority of reports a systolic PA pressure of 50 mm Hg has been taken to denote “significant” PH.3*5,6s ” We have taken 50 mm Hg of PA systolic pressure to denote “significant” PH. PH in ASD may be related to a large pulmonary flow (hyperkinetic PH) or may be due to the development of pulmonary vascular disease. Arbitrarily PH has been classified as obstructive3 and due to pulmonary vascular disease when the pulmonary vascular resistance exceeds 5 units (400 dynes . set . cmw5).

Frequency of PH. The frequency of PH in isolated secundum ASD has been difficult to assess from the literature. Some series have included ostium pri- mum defects and associated conditions like mitral stenosis.3’ 12, 14, 2o Some of the reports are on patients who have undergone surgical correction,5-8*21 while others include both surgical and nonsurgical patients.‘s3’4*12 Sixteen percent of the 225 patients reported by Besterman3 had PH. Of those with PH, 73 % had the obstructive type and 17 % the hyperki- netic type while in four others PH was associated with the Lutembacher syndrome. In our series the pulmonary vascular resistance exceeded 5 units in 78.8% and the remaining 20.2% presumably had hyperkinetic PH. PH has been reported in 8.3% to 20% of patients in other series,5-7 while it was present in 17 % of our patients. The frequency of PH can be expected to increase with age and has done so in all reports. In our series, as well, the frequency of PH was higher in older patients (p < O.Ol), although it was present in 13% in the first decade.

Volume 105

Number 6

Prevalence of pulmonary hypertension in ASD 955

Table V. Comparative frequency of pulmonary hypertension

Authors Criteria of PH Age grow (yr) Frequency (%)

Liddle et al.’ Present series Evans et al.‘* Present series Zaver and Nadas19 Present series

SPAP > 50 SPAP > 50 SPAP > 50 SPAP > 50 Pulmonary systolic pressure >0.5 ) SPAP > 50

>16 >20 <16 <20 All age groups All age groups

8 21

p < 0.001

5 13.5

p < 0.05

g.6 p < 0.01 17

SPAP = systolic pulmonary artery pressure (mm Hg).

PH in young patients. A comparative study of PH in different age groups has been difficult since most of the reports are on older patients and the age groups are not clearly separated in many series.3-5*12 Only one of the patients with PH reported by Rahimtoola et al8 was between 10 and 20 years of age, and the remaining 54 patients were all older. In another report there was only one patient in the first two decades out of 15 with PH,5 whereas 13% of the patients in the first decade and 14% in the second decade in our series had PH. In the reports from the literature PH in the first and second decades has been rare.2’ 7,% 22

Eisenmenger reaction. The Eisenmenger reaction with shunt reversal was present in 6% of 324 patients with atrial septal defect reported by Wood2 and in 6% of the 225 patients reported by Bester- man.3 The comparative frequency of the Eisenmen- ger reaction in atrial septal defect is shown in Table IV. The overall frequency in our series in all age groups was 9 % . The striking difference was that out of our 61 patients with shunt reversal at rest, 20% were in the first decade and 31% in the second decade. There was no significant difference when compared to those in the third decade and beyond showing that the Eisenmenger reaction was as com- mon in our younger patients. In the report by Wood,2 patients with ASD when first seen had an average age of 26 years and developed the Eisen- menger reaction at an average age of 35 years.

Surgical rlsk and follow-up. The surgical mortality rate in the presence of PH has ranged from 16% to 70% .5,1,8,10* 23 Out of our 118 patients with PH, 31 had surgery and three died (mortality rate 9.6%). Rahimtoola et al.’ have suggested that patients with a pulmonary vascular resistance over 8 units (640 dynes . set . cme5) should probably be considered inoperable, since of their 20 patients with a pulmo- nary vascular resistance exceeding 8 units, 10 died and of the :LO survivors four did not derive any benefit. Following surgery, regression of the PH is common but it is not always uniform or complete.6” Recatheterization studies have been carried out in

Table VI. Main pulmonary artery at autopsy

Pulmonary:

Age PA pressure systemic Type of PA (yr) Sex (mm Hd flow ratio at autopsy

6 M 85155 2.8: 1 Transitional resembling fetal

9 F 65135 1.4:1 Transitional 10 M 85140 1.5:1 Transitional 27 F 110/50 Shunt Adult

reversal

PA = Pulmonary artery.

only a few of our surgical patients. However, there was symptomatic improvement in all and regression of R in lead V, in 85%.

PH in ASD. It is well known that many patients are able to tolerate large pulmonary flows in atrial septal defect without developing pulmonary vascu- lar disease. Forfang et aL21 reported on 93 patients over the age of 40 years at the time of surgery, and PH was present in only one of their patients. Swan et al.‘O have shown that for equivalent pulmonary flows, PH is most common in ventricular septal defects and least common in atrial septal defects. PA systolic pressure over 40 mm Hg was present in 16.6 % of their patients with ASD, 52% with an aortopulmonary communication, and 90% with ven- tricular defects. There is no relationship between the size of the defect and the development of pulmonary hypertension and the Eisenmenger reac- tion in ASD.2

Altitude and PH. Dalen et al.,24 in patients less than 20 years of age, found PH more frequently in those who lived at an altitude of 4000 feet or more (11 of 53) as compared to those who lived at an altitude of 2000 feet or less (3 of 49). In another report on 111 patients with a mean age of 7 years, the frequency of PH was 9.7% in those who resided at moderate or high altitude and was higher than in those staying at sea level.” Thus chronic hypoxia at moderate alti- tudes can result in PH in ASD. However, none of our patients were living at such elevations.

956 Cherian et al. June. 1983

American Heart Journal

Respiratory infections and PH. The role of recurrent respiratory infections in the development of PH is not clear.3*24 The pulmonary vascular resistance can increase during respiratory infections and regress later, and cardiac catheterization carried out even a week after the respiratory infection has, in our experience, given rise to misleading high results. Untreated recurrent respiratory infections in our patients may be one of the causes for the high frequency of PH particularly in the younger age group.

Pulmonary flow and PH. Edwards25 has shown that the pathologic changes in the pulmonary vascula- ture in patients with atria1 septal defects and PH are primarily intimal, the degree of intimal abnormality reflecting the severity of the PH, whereas medial hypertrophy predominates as an expression of PH in those with ventricular septal defects. The cause of this intimal reaction is not clear. The early histologic changes are at the arteriolar junction with the small arteries and may be the result of the increased pulmonary flow. Once established the increase in pulmonary vascular resistance may be gradual over 5 to 10 years but may also occur in an accelerated fashion. The fact that progressive pulmonary vascu- lar changes do not develop in all patients with a large pulmonary flow does not argue against hyper- reactivity of the pulmonary vascular bed as a response to the prolonged hypercirulatory state in the pulmonary circulation being the mechanism of the PH in the majority of patients with atrial septal defects who develop this complication. Some reports have shown that PH is more frequent in patients with high superior vena caval defects associated with partial anomalous venous drainage.2, 6, 2o This was not so in our patients.

Persistent fetal pulmonary vascular pattern. In Bes- terman’s series, one group of patients with PH was younger, had relatively less cardiac enlargement, and had a higher pulmonary vascular resistance. He felt that some of these might be examples of “con- genital” PH, as a result of persistence of the fetal pulmonary vascular pattern. Examination of the elastic tissue of the pulmonary trunk allows one to decide whether the PH has been present from birth or whether it has developed later after the natural regression in PA pressure.26 When PH has been present from birth the elastic tissue of the main PA shows a structure similar to that of the aorta-the so called fetal pattern. As seen from Table VI, the PA was studied at autopsy in four of our patients with PH. A 27-year-old patient had the adult-type PA while in the other three younger patients, aged 8, 9, and 10 years, the PA was of a transitional type

between the fetal and the adult pattern, suggesting that the rise in pulmonary vascular resistance in these young patients was present from an early age and probably from birth. It is difficult to know how important this mechanism is in the development of PH in young patients with atria1 septal defects. At times, there is also an unnatural progression in PH. One of our patients, a young girl, at the age of 7 years had a PA pressure of 20110 mm Hg and a pulmo- nary: systemic flow ratio of 2.8: 1. Four years later, she was reinvestigated and the PA pressure was 88/40 mm Hg with a pulmonary: systemic flow ratio of 3.2: 1. Surgery was not advised in view of the unusual progression and over the next 3 years she developed shunt reversal. This is an unusual exam- ple of rapid development of severe PH in a young patient which was clearly not related to persistence of the fetal pulmonary vascular pattern.

Ethnic variations in PH. It may be argued that the higher incidence of PH in our patients may be the result of selective referral. However, only two of these patients had been catheterized elsewhere and there is no reason to believe that our series repre- sents a selective referral of those suspected to have PH. We have reported on the high frequency of primary pulmonary hypertension in India2’ and it is conceivable that there may be ethnic variations in the development of PH in other cardiac conditions as well.

Pulmonary vascular resistance in secundum ASD. The pulmonary vascular resistance in isolated secundum atria1 septal defects may behave in differ- ent ways.” In some it may remain normal for life despite high pulmonary flows. In some others it may be slightly raised from birth resulting in hyperkinet- ic PH which persists unchanged. In others the hyperkinetic PH progresses to pulmonary vascular disease and results in obstructive PH. In a few, the pulmonary vascular resistance may remain high from birth.

Conclusions. Our results show that there is a significantly high frequency of PH in our young patients with secundum ASD. In the younger age group some of these patients may represent a persis- tence of the fetal pulmonary vascular pattern. The relationship, if any, of untreated recurrent respira- tory infections or ethnic variations in susceptibility is not clear.

We thank Mrs. Wilma Di Cicco for her help in typing this manuscript.

REFERENCES

1. Campbell M, Neil1 C, Suzman S: The prognosis of atria1 septal defect. Br Med J 1:1375, 1957.

2. Wood P: The Eisenmenger syndrome or pulmonary hyper-

Volume 105

Number 6 Prevalence of pulmonary hypertension in ASD 957

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

tension with reversed central shunt. Br Med J 2:701, 755, 1958. Besterman E: Atria1 septal defect with pulmonary hyperten- sion. Br Heart J 23:587, 1961. Dalen JE, Haynes FW, Dexter L: Life expectancy with atria1 septal defect-influence of complicating pulmonary vascular disease. JAMA 200:442, 1967. Liddle HV, Meyer BW, Jones JC: The results of surgical correction of atria1 septal defect complicated by pulmonary hypertension. J Thorac Cardiovasc Surg 39:35, 1960. Cohn LH, Morrow AG, Braunwald E: Operative treatment of atria1 septal defect: Clinical and haemodynamic assessment in 175 patients. Br Heart J 29:725, 1967. Coles J, Sears G, Macdonald C: Atria1 septal defect compli- cated by pulmonary hypertension-a long term follow-up. Ann Surg 166:496, 1967. Rahimtoola SH, Kirklin JW, Burchell HB: Atria1 septal defect. Circulation 38:(suppl 5):2, 1968. Beck W, Swan, HJC, Burchell HB, Kirklin JW: Pulmonary vascular resistance after repair of atria1 septal defects in patients with pulmonary hypertension. Circulation 22:938, 1960. Swan HJC, Zapata-Diaz J, Burchell HB, Wood EH: Pulmo- nary hypertension in congenital heart disease. Am J Med 16:12, 1954. Khoury GH, Hawes CR: Atria1 septal defect associated with pulmonary hypertension in children living at high altitude. J Pediatr 70:432, 1967. Bedford DE, Sellors TH: Atria1 septal defect. In Modern trends in cardiology. London, 1960, Butterworth & Co, Ltd, p 138. Yang SS, Bentivoglio LG, Maranhao V, Goldberg H: From cardiac catheterization data to haemodynamic parameters. Philadelnhia. 1972, F A Davis Comoanv. D 12. BedfordADE,,‘Sellors TH, !jomerville W: Belcher JR, Bester- man EMM: Atria1 septal defect and its surgical treatment. Lancet 1:1255, 1957.

15. Mark H: Natural history of atria1 septal defect with criteria for selection for surgery. Am J Cardiol. 12:66, 1963.

16. Gault JH, Morrow AG, Gay WA Jr, Ross J Jr: Atria1 septal defect in patients over the age of forty years: Clinical and haemodynamic studies and the effects of operation. Circula- tion 37:261, 1968.

17. Young D, Mark H: Fate of the patient with the Eisenmenger syndrome. Am J Cardiol 28:658, 1971.

18. Evans JR, Rowe RD, Keith JD: The clinical diagnosis of atria1 septal defect in children. Am J Med 30:345, 1961.

19. Zaver AG, Nadas AS: Atria1 septal defect-secundum type. Circulation 32(suppl 3):24, 1965.

20. Burchell HB: Studies in pulmonary hypertension in congeni- tal heart disease. Br Heart J 21:255, 1959.

21. Forfang K, Simonsen S, Andersen A, Efskind L: Atria1 septal defect of secundum type in middle age: Clinical results of surgery and correlations between symptoms and hemody- namics. AM HEART J 94:44, 1977.

22. Dexter, L: Atria1 septal defect. Br Heart J 18:209, 1956. 23. McGoon DC, Swan HJC, Brandenburg RO, Connolly DC,

Kirklin JW: Atria1 septal defect: Factors affecting the surgi- cal mortality rate. Circulation 19:195, 1959.

24. Dalen JE, Bruce RA, Cobb, LA: Interaction of chronic hypoxia of moderate altitude on pulmonary hypertension complicating defect of the atria1 septum. N Engl J Med 266:272, 1962.

25. Edwards JE: Functional pathology of the pulmonary vascular tree in congenital cardiac disease. Circulation 15:164, 1957.

26. Heath D, DuShane JW, Wood EH, Edwards JE: The struc- ture of the pulmonary trunk at different ages and in cases of pulmonary hypertension and pulmonary stenosis. J Path01 Bacterial 77:443, 1959.

27. Cherian G, Abraham MT, Sukumar IP, Krishnaswami S, Abraham KA: Idiopathic pulmonary hypertension-a study of 94 natients. Abstracts I. VIII. World Coneress of Cardiol- ogy, l-978, p 272.