thepulmonary circulation in fibrosis · diagram showing musclefibre distribution in small pulmonary...

Thorax (1975), 30, 285.

The pulmonary circulation in cystic fibrosisDAVID RYLAND and LYNNE REID

Department of Experimental Pathology, Cardiothoracic Institute, Brompton Hospital,London SW3

Ryland, D. and Reid, Lynne (1975). Thorax, 30, 285-292. The pulmonary circulationin cystic fibrosis. The hearts and lungs of 36 patients dying of cystic fibrosis have beenstudied to establish the relationship between right ventricular hypertrophy (RVH),pathological changes in the pulmonary circulation, and the clinical features.The presence and degree of RVH were measured by Fulton's technique of weighing

the ventricles separately. Of the subjects who died after the age of 3 years, one in sixhad no RVH, although the mean age of this group was not significantly different fromthat of the remainder.

There was no correlation between duration of cyanosis, haemoglobin levels, and RVH.Although not statistically significant, the cases without RVH tended to have had clubbingof the finger-nails for longer periods before death.The electrocardiogram was useful in the diagnosis of RVH. Right ventricular hyper-

trophy was common in children with lungs of large volume as judged by the radio-graphic centile of lung length.

Cases with RVH show reduced background haze in the arteriogram and fewerarteries per unit area of lung. For the first time thickening of the medial muscle layerproportional to the degree of RVH has been demonstrated, only in the smaller arteries.Arterial subintimal fibrosis is more common in cases with RVH, as is thickening of thewalls of small pulmonary veins.The implications of these findings are discussed.

Since the description of cystic fibrosis (CF) byAndersen in 1938, the development of cor pul-monale and pulmonary hypertension has beenrecognized as an important feature in the naturalhistory of the disease (Andersen, 1938; Wiggles-worth, 1946; Andersen, 1949; May and Lowe,1949).Royce (1951) stated that chronic 'cor pul-

monale' was to be expected in 70% of childrendying of CF; a similar incidence was found bySchwachman and Kulczycki (1958). Physiologicalstudies of the pulmonary circulation in cysticfibrosis (Goldring et al., 1964; Kelminson, Cotton,and Vogel, 1967) suggested that hypoxia was theprincipal stimulus to the production of pulmonaryhypertension in CF and that the latter was some-times partially reversible, although clinicalassessment of pulmonary hypertension during lifein CF patients can be difficult (Siassi, Moss, andDooley, 1971).

Morphological observations on the pulmonarycirculation in CF were limited until 1963 when

Bowden and Wyatt found right ventricularhypertrophy (RVH), assessed by right ventricularwall thickness, in a group of seven subjects dyingof CF; they considered that this was due tohypoxic pulmonary hypertension and the openingup of anastomoses between the pulmonary andbronchial artery systems. They did not find grossdestruction of the parenchyma or of the capillarybed.

Esterly and Oppenheimer (1968) found signifi-cant parenchymal destruction in only three of84 cases, which they thought pointed to the im-portance of the pulmonary vessels in the patho-genesis of RVH. Kelminson et al. (1967) reportedmedial hypertrophy of the pulmonary arteries inone patient dying of CF.Davies (1969) reported detailed quantitative

analysis of the pulmonary arterial circulation infour cases of CF. While only two had RVH atnecropsy, all four showed an increase in thethickness of the medial muscle coat of the pul-monary arteries, and extension of muscle into

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D. Ryland and Lynne Reid

vessels smaller than those containing muscle inthe normal subject. Paradoxically the greatestincrease in pulmonary artery muscle was foundin one of the two cases with no RVH.More recently, Symchych (1971) reported in-

creased medial thickness in the pulmonary arteriesof nine CF cases when compared with controls.Neither he nor Davies established any correlationbetween degrees of arterial wall thickening andthe degree of RVH. Both authors reported thegreatest changes in the smallest pulmonaryarteries.

PRESENT STUDY

In this study the hearts and lungs of 36 CFpatients were studied using Davies' accuratequantitative morphometric techniques. The clini-cal histories, chest radiographs, electrocardio-grams, and certain physical signs during life werealso assessed.

It was hoped that close statistical analysis of theresults in this larger group would elucidate therelationship between the development of cor pul-monale (defined by the World Health Organiza-tion Report No. 213 (1961) as right ventricularhypertrophy of pulmonary origin), its clinicalcourse, and the changes in the vascular tree.

MATERIAL AND METHODS

In all 36 cases the heart was obtained. In 30 casesboth lungs were available; in the remaining sixcases only one lung. The clinical history wasassessed in every case from the hospital recordsand consultation with the patients' physicians.

Postero-anterior chest radiographs were ana-lysed using the centile standards for 'heartdiameter' and 'lung length' prepared by Simonet al. (1972). The last chest radiograph takenbefore death was analysed in 24 of the cases. Forthe others, radiographs were either not availableor were not included because the patient suc-cumbed before the age of 6 years, below whichSimon's standards are not applicable.

Electrocardiograms had been recorded in only15 patients. These were measured to obtain theangle of the frontal axis of the main ventriculardeflection recorded from the limb leads. The sizeof this angle has been shown (Millard, 1965) to bethe most reliable evidence of the presence of RVHin adult chronic bronchitis.

PATHOLOGICAL TECHNIQUES

HEART WEIGHT The presence and degree of RVHwere assessed by the method of Fulton,

Hutchinson, and Jones (1952). This depends onweighing the right ventricle (RV) separatelyfrom the left ventricle and the interventricularseptum (LV+ S). In the adult, Fulton used boththe ratio of LV+S to RV and the absoluteweights of the right ventricle as indices of RVH.Since in the child no range of normal weightsfor cardiac chambers at different ages has beenestablished, in the present study the ratioLV+S: RV was used, a value of less than 2: 1indicating RVH. In early infancy, right ventri-cular predominance is normal, the 'adult' ratiobetween the chambers being achieved by the thirdor fourth month of life (Recavarren and Arias-Stella 1964; Shinebourne and Howarth, 1973).Therefore the patients were grouped according toboth age and heart weight.

LUNG MORPHOLOGY The methods used in thepreparation and morphological analysis of thelungs have been fully described elsewhere (Elliott,1964; Davies, 1969; Davies and Reid, 1970; Hislop,1971). The arteries of one or both lungs of eachcase of the present group were injected with awarm barium/gelatine mixture under a constantpressure of 100 cm of water. In 12 cases the veinsof one lung were injected by the same technique.The medium penetrates to vessels of about 15 ,umdiameter. Injection under a standard hypertensivepressure ensures maximal distension of all thevessels in the lungs and permits valid comparisonbetween cases.

Immediately after injection the lungs were in-flated by running 10% formal saline solution intothe main bronchus from a pressure head of 45 cmuntil the pleura was tense. No attempt was madeto inflate the lungs to a particular volume, sincesmall changes in volume would affect linear di-mensions very little.The lung volume was measured by water dis-

placement and allowance was made for shrinkageduring fixation. After fixation the lung was cutinto 1 cm thick slices (0 5 cm in the smaller lungs);the relative volumes occupied by the largerstructures (arteries, veins, and bronchi) and byparenchyma were measured by a point-countingtechnique (Dunnill, 1962; Hislop and Reid, 1970).Four blocks of tissue (2 cmX2 cm) were takenfrom each lung chosen by the stratified randomselection procedure of Dunnill (1962) and Weibeland Gomez (1962). Microscopic analysis consistedof measurement of:

(1) arterial or venous density, that is, thenumber of vessels below 500 ,um diameterper mm2 of lung (corrections were made for

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The pulmonary circulation in cystic fibrosis

shrinkage during fixation and cutting of thesections);

(2) medial muscle wall thickness of the arteriesor veins in each section. This was expressedas the ratio of medial thickness measuredbetween internal and external elasticlaminae, to the external diameter of thevessel. Grouping the arteries or veins intosize ranges allows wall thickness at varioussize levels to be calculated for each case;

(3) population counts. Elliott (1964) showed thatarterial wall muscle does not end abruptly,but that the complete muscular sheath givesway to a spiral of muscle which persistsmore distally before the artery becomestruly non-muscular. Thus small artery wallshave been classified as muscular, partiallymuscular or non-muscular (Fig. 1). Ana-lysis by size and structure of all arteries in a

section yields a 'population' count, enablingthe percentage of partially muscular arteriespresent in a given size range to be assessed.This indicates accurately the penetration ofmuscle into small arteries. It may be notedthat the diameter of the smallest muscularartery and the largest non-muscular arterynecessarily refers to single vessels, while thesize range at which partially musculararteries are most common depends on alarge number of vessels. Since this featureof the population count was most reliableand least subject to variation, it was used toassess peripheral extension of muscle;

(4) intimal changes. The presence of intimalthickening and of subintimal longitudinalmuscle formation was noted. This changewas rare (affecting fewer than 5% of ves-

sels), and its distribution patchy, beingalmost always in the most damaged region

MUSCULAR PARTIALLY NONMUSCULAR MUSCULAR

Copillary

CROSSSECTION

FIG. 1. Diagram showing muscle fibre distribution insmall pulmonary artery wall,

of lung. This made precise quantificationdifficult. The number of blocks of tissue inwhich these changes were seen was esti-mated for each case.

RESULTS

On the basis of heart weights the subjects weredivided into five groups (Table):

TABLECYSTIC FIBROSIS PATIENTS

Average LV + SGroup Age Range

RV

A Neonate (1) 5 days - 1f8B Infants (3) 3-3 mth 3-4 mth 2-8C Non-RVH (6) 12yr 11 mth 5-21 yr 2-56D MildRVH (12) 10yr 8mth 4-19yr 1-68E SevereRVH (14) 10yr lOmth 3-20yr 1-22

A a neonate of 5 days who died of meconiumileus. The ratio (LV+S/RV) of 1-8 indicatesthe right ventricular predominance normalat this age;

B three children dying of respiratory infectionsbetween the ages of 3 and 4 months. All hadattained normal adult (LV+S/RV) ratios;

C six patients between 5 and 21 years. All hadthe severe lung changes that frequentlycause death in cystic fibrosis. Despite thelong duration of their disease none had RVH.

Groups D and E included 26 patients inwhom RVH was found at necropsy. Thesewere divided into mild RVH (group D)whose LV+S/RV ratios lay between 2-1 and1-4, and severe RVH (group E) whose ratioswere below 1 4.

Thus of the 32 children who died after the ageof 1 year, six (18%) had not developed RVH. Nosignificant difference was found between the meanage at death for groups C, D, and E.

CLINICAL FEATURESHAEMOGLOBIN None of the children at any stagehad haemoglobin levels in excess of 16-6 g/dl(110%). Unfortunately, haematocrit measure-ments were not usually available. In two casesserum iron levels had been measured and were inthe low normal range.

CYANOSIS In the absence of any other relativedata it seems justified to regard the mean durationof cyanosis in each group. Although there waswide variation between cases, somewhat longerperiods of cyanosis were recorded in patients withRVH, although the difference from the othergroups was not statistically significant,

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CLUBBING OF FINGER-NAILS In contrast to cyano-sis, the duration of finger clubbing was muchlonger in some of the non-RVH cases than inthose with RVH. Although a significant correla-tion was not demonstrated it seems that the devel-opment of finger clubbing does not indicate theonset of RVH.

RV HYPERTROPHY AND RV FAILURE The intervalbetween clinical diagnosis of RVH and death andthe duration of persistent right ventricular failurewere determined from the clinical notes. Bothconditions are difficult to diagnose in CF, the firstbecause overinflation of the lungs makes palpa-tion of the heart difficult, the second because fluidretention can be a feature of severe obstructivelung disease.RVH was diagnosed in life in four of the 12

mild RVH cases, and in three of the 14 severeRVH cases. Terminal right ventricular failure wasmore frequently diagnosed-in two of the threeneonates, in three of six non-RVH, seven of 12mild RVH, and 11 of 14 severe RVH cases. Themean duration of failure was longest in the severeRVH cases and shortest in the non-RVH cases,although the difference did not reach statisticalsignificance.

INFECTION WITH PSEUDOMONAS PYOCYANEA Thisorganism is commonly found in the sputum ofpatients with severe cystic fibrosis (Lawson, 1969;Mearns, Hunt, and Rushworth, 1972). It had beenisolated in all except the neonate and two infants,but no correlation was found between the durationof this infection and the presence or degree ofRVH.

HEIGHT AND WEIGHT OF PATIENTS The childrenwere underweight for their age. Their weightswere all below the 25th centile on the expectedweight charts (Tanner, Whitehouse, and Takaishi,1966), while most were at or below the 10th cen-tile. The children were also shorter than expected.Most were between the 3rd and 25th centilevalues on the expected height charts, six were atthe 50th centile value, and only one was at the75th. Children with RVH were no more stuntedthan those without RVH.

ELECTROCARDIOGRAMS Electrocardiograms wererecorded in 15 cases. A QRS frontal axis of morethan 90° (right axis deviation) was accepted asevidence of RVH. Right axis deviation was notseen in the three cases without RVH at necropsy.

Of the 12 cases with RVH at necropsy, seven hadright axis deviation on the ECG. Thus the ECGdid not detect some cases of RVH, but in 10 therewas agreement between elecrocardiographic andpathological findings. No 'false' positives wereseen in that right axis deviation was always associ-ated with RVH.

RADIOGRAPHIC STUDIES In 25 cases (those dyingaged 6 years or more) 'heart diameter' and 'lunglength' were measured (see Fig. 2) on the lastchest radiograph before death, using the techniquedescribed by Simon et al. (1972), and comparedwith the centile charts.

It will be seen that increase in heart diameter isa poor indicator of RVH. None of the mild RVHcases and only three of the severe RVH casesshowed this change. Lung length correlates betterwith RVH. This measurement was below the 50thcentile in all non-RVH cases, while only four ofthose with RVH had small lungs. Thus in 21 of25 cases there was a correlation between RVH andlung length.

97 xx . x

90 x x xxxx

75 xxxx . xx

w-50 x xzw

25 xxx

10 .. x .. x

3 . x ... ... xxx

C D EGROUPS

FIG. 2. Centile values for radiographic lung lengthand heart diameter in the three older groups ofchildren: 0 heart diameter; X lung length.

PATHOLOGICAL FINDINGS

Lung volume before fixation varied widely buttended to be smaller in non-RVH cases althoughno statistically significant correlation emerged.

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MACROSCOPIC POINT COUNTING Serious loss ofperipheral lung tissue, that is, the alveolar region,henceforth referred to as 'parenchyma', was un-common. The mean percentage of lung volumeoccupied by arteries was calculated for each ofthe five groups of patient. A significant correlationemerged between reduction in volume of arteriesand the appearance of RVH (P<005) (FIG. 3).

ARTERIAL WALL THICKNESS The mean arterialwall thickness for vessels from 1000 um diameterdown to 25 ,um grouped by size are shown forthe three childhood groups (Fig. 5).

If

9.

9.

8

E:3 7.

-60 6

+

I

I

A B CGROUPS

o r0

'C

I ID E

FIG. 3. CF patients-macroscopic arterial volume.

ARTERIAL DENSITY The number of arterial out-lines of less than 500 um diameter was calculatedper square millimetre fresh inflated lung. In eachpatient it varied greatly from one microscopic fieldto another, as did the mean values for each lobe.The mean arterial density was calculated for

each case from all counts, and a close correlationemerged between arterial reduction and degree ofRVH. Figure 4 shows the mean values for thefive patient groups. Thus macroscopic and micro-scopic analyses both reveal a correlation betweenRVH and a reduced pulmonary arterial tree. Nosuch correlation was found with vein density.

E5-E

x 4 -w4

3-

2

* Severe RVHo MildA Non is

x Normal 9yrs old

xv

x- - -- x- ---

-75 -150 -300 -500 -800 1000'

-50 -100 -200 -400 -600 -1000Artery diameter (mp)

FIG. 5. CF patients-arterial wall thickness.

In the smaller arteries (25-50 ,tm and 50-75,um) increasing wall thickness correlates signifi-cantly (P<0-02) with the degree of RVH; althougheven in cases with no RVH, wall thickness isgreater than normal (Elliott, 1964; Davies andReid, 1970). When larger size ranges are con-sidered the correlation is less close and, in arteriesabove 300 ,um, fails to reach significance.

VEIN WALL THICKNESS Figure 6 shows the meanvein wall thickness for veins 25-50 ,m in diameter

9

07

0x

NI 5+ I

I II

A B C D EGROUPS

3

* VEINS 25-50Om,vDIAMETER

*S.

*

* .

* *0* t.

RVH + 1< RVH* <-:-> RVH

1.0 1.5 2.00

LV+SRV

FIG. 4. CF patients-microscopic arteries per square FIG. 6. Mean wall thickness of the smallest pul-millimetre. monary veins in the 12 cases studied.

5-

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in each of the 12 cases injected. In this smallestsize range the correlation between wall thicknessand RVH reaches significance of P<001, that is,somewhat greater than that of arterial wall thick-ness and RVH. In larger veins the correlationbecomes less significant and is not apparent abovediameters of 200 ,cm.

POPULATION COUNTS As previously described, thesize range in which the maximal concentration ofpartially muscular arteries occurs is the best indi-cation of peripheral extension of muscle. Becausemuscle usually extends with age only groups C, D,and E can be compared with each other (Fig. 7).Peak partially muscular arterial concentrationsare found in smaller size ranges when RVH ispresent, indicating peripheral extension of muscle.

* x XX X0

0

E e K KXXXX

A B C D Eneonate infonts non RVH mild RVH severe RVH

FIG. 7. Population count-size range of peak con-centration of partially muscular arteries.

INTIMAL THICKENING AND SUBINTIMAL LONGI-TUDINAL MUSCLE Intimal changes were almostalways found in severely affected areas of lung andwere patchily distributed. A progressive increasein the mean number of blocks of lung tissueshowing these changes was found in groups C, D,and E (Fig. 8) and is significant at the P<0-02level.

DISCUSSION

It is striking that six of the 36 children in thisseries died from extensive lung disease withoutdeveloping right ventricular hypertrophy althoughall had some degree of pulmonary artery musclehypertrophy. This confirms the earlier report fromour department that longstanding lung disease isnot necessarily associated with RVH and that

5

4

(a

0

-3 3

o-2

a 2

I2

* intimal thickening

x longitudinal muscle

- .-x B x .

A B

T II

IT

C DGROUPS

II I

I

E

FIG. 8. Microscopic analysis-mean number ofblocks (out of 8) showing (1) intimal thickening, and(2) longitudinal muscle.

increased muscularity of the heart and pulmonaryarteries do not necessarily go together (Davies,1969).The development of cardiac changes is not

directly related to age, there being no significantdifference in age at death between the non-RVH,mild RVH, and severe RVH groups.

Clubbing of the finger-nails was reported, sub-ject to errors of recording or observation, aspresent for a longer period in most of the non-RVH cases although this correlation did not reachsignificance. It is clear that clubbing does notsignify either a poor prognosis or the onset ofRVH.

Right ventricular hypertrophy and failure wererarely recorded during life, perhaps because thepulmonary signs overshadow the cardiac, and thealterations in circulating fluid volume make clini-cal diagnosis of these conditions difficult.

It might seem that the relatively low haemo-globin measurements in the CF children excludepolycythaemia but Caplan and Gross (1968) havedemonstrated that for normal children values arelower than for the adult. They reported a meanhaemoglobin level of 12 7 g/dl in a group of 87normal children aged 5-16 years, and somewhathigher levels in a similar age group of CF children,but in the latter the haemoglobin levels did notrise to the same extent as the haematocrit becausemean corpuscular haemoglobin concentration wasreduced. Caplan and Gross (1968) also demon-strated higher haemoglobin figures in CF patientswith arterial oxygen desaturation than in thosewithout. In our cases, severe RVH was associated

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with higher haemoglobin levels, apparently cor-roborating their findings. It is clear that poly-cythaemia in children with CF is less striking thanin adult chronic bronchitics, where an increase inred cell number is associated with much higherlevels of haemoglobin and of corpuscular haemo-globin concentration than in cystic fibrosis.From all patients over the age of 1 year at

death Pseudomonas pyocyanea had been culturedfrom the sputum, but in most cases other organ-isms, usually Staphylococcus aureus, were alsofound.Of all the investigations carried out in this series

of cystic fibrosis, increase in radiological estima-tion of 'lung length' seems to correlate best withthe presence of RVH. This supports the necropsyfinding that the lungs from RVH cases tend to bebulkier than those from non-RVH cases. It maybe that the vessels of an undersized lung are in-capable of developing the increased muscle neces-sarily associated with the development of RVH.This is the reverse of adult chronic bronchitiswhere it is the large lung of severe panacinaremphysema that lacks the arterial muscle and thusoffers some 'protection' from RVH.

Electrocardiographic analysis seems as accuratein the detection of childhood as of adult RVH.Every patient showing right axis deviation on theECG had an abnormally heavy right ventricle atnecropsy but the ECG failed to detect five of the12 cases with RVH. Thus ECG changes are goodevidence of RVH, but their absence does not pre-clude its presence.

THE PULMONARY CIRCULATION The reduction ofthe arterial tree in CF could be the result of hypo-plasia arising from the pulmonary disease. All themajor pulmonary arterial branches (which developin utero) were present but reduced in size, andmore severely reduced when RVH was present.The smaller arteries which develop in post-natallife were reduced in number in all cases of CF.When RVH becomes more severe the reductionin arterial number becomes progressively moremarked.

These changes were most apparent in the partsof the lung that were severely damaged and pre-sumably hypoxic. Although wide variations werefound in each lung, the overall arterial wall mus-cularity has, for the first time, been shown to cor-relate with the state of the right ventricle in CF.Increase in muscular wall thickness was found inall CF patients but was more marked in those withRVH. Although a statistically significant correla-tion was found between the two features, the

variation between cases made it impossible tospecify a wall thickness which separates 'RVHcases' from 'non-RVH cases'. This is probablydue to the inherent difficulties of applying asampling technique to lungs so patchily affectedas in CF.The results suggest that increasing arterial wall

thickness may at first be tolerated by the heart,but that RVH is induced when the thickness isincreased beyond a certain point. The increase inarterial muscle is perhaps only one factor in thepathogenesis of RVH.

Peripheral extension of arterial muscle wasdemonstrated by population counts which showedthat the peak concentration of partially musculararteries occurred at smaller size ranges in caseswith RVH than in those without. That peripheralextension did occur is also suggested by the simi-larity of the size distribution of the vessels com-pared with normal cases. If the CF vessels wereless distensible, apparent peripheral extensioncould be explained by 'larger' vessels with mus-cular walls not distending, but this would havereduced the numbers of vessels in the largerranges, which was not observed.

In contrast to the arterial tree, no reduction wasfound in the volume of veins, nor in the numberof small veins per unit area of lung. This may bethe result of distance between vein and airway inthe lung in contrast to the proximity of artery toairway. A bronchus plugged by mucus would, ofnecessity, produce considerable hypoxia in thewall of its accompanying artery. The veins, how-ever, tend to run between the acini more or lessequidistant from a number of bronchial pathways.In a patchily distributed disease such as CF theveins would be more uniformly affected than thearteries. Indeed, much greater variation in wallthickness was found in the arteries. This may bethe reason for the closer correlation between veinwall thickness and RVH. It seems that in cysticfibrosis the arterial system either fails to developcompletely, or else many small branches disappearas the disease progresses.

REFERENCES

Andersen, D. H. (1938). Cystic fibrosis of the pancreasand its relation to celiac disease; clinical andpathologic study. American Journal of Diseasesof Childhood, 56, 344.(1949). Therapy and prognosis of fibrocystic

disease of the pancreas. Pediatrics, 3, 406.Bowden, D. H. and Wyatt, J. P. (1963). Pathogenesis

of cor pulmonale in cystic fibrosis (abstract).Circulation, 28, 693.

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Caplan, A. and Gross, S. (1968). Hematologic andserologic studies in cystic fibrosis. Journal ofPediatrics, 73, 540.

Davies, G. (1969). Lung damage, hypoplasia and rightventricular hypertrophy in cystic fibrosis. In Pro-ceedings of the Fifth International Cystic FibrosisConference, edited by D. Lawson, p. 350. CysticFibrosis Research Trust, Stuart House, London.and Reid, L. (1970). The growth of the alveoliand pulmonary arteries in childhood. Thorax, 25,669.

Dunnill, M. S. (1962). Quantitative methods in thestudy of pulmonary morphology. Thorax, 17, 320.

Elliott, F. M. (1964). The pulmonary artery system innormal and diseased lungs; structure in relationto pattern of branching. Ph.D. thesis, Universityof London.

Esterly, J. R. and Oppenheimer, E. H. (1968). Obser-vations in cystic fibrosis of the pancreas. III.Pulmonary lesions. The Johns Hopkins MedicalJournal, 122, 94.

Fulton, R. M., Hutchinson, E. C., and Jones, A. M.(1952). Ventricular weight in cardiac hypertrophy.British Heart Journal, 14, 413.

Goldring, R. M., Fishman, A. P., Turino, G. M.,Cohen, H. I., Denning, C. R., and Andersen,D. H. (1964). Pulmonary hypertension and corpulmonale in cystic fibrosis of the pancreas. Jour-nal of Pediatrics, 65, 501.

Hislop, A. (1971). The fetal and childhood develop-ment of the pulmonary circulation and its dis-turbance in certain types of congenital heartdisease. Ph.D. thesis, University of London.and Reid, L. (1970). New pathological findings

in emphysema of childhood. I. Polyalveolar lobewith emphysema. Thorax, 25, 682.

Kelminson, L. L., Cotton, E. K., and Vogel, J. H. K.(1967). The reversibility of pulmonary hyper-tension in patients with cystic fibrosis. Observa-tions on the effect of tolazoline hydrochloride.Pediatrics, 39, 24.

Lawson, D. (1969). Panel discussion on microbiologyand chemotherapy of the respiratory tract incystic fibrosis. Proceedings of the Fifth Interna-tional Cystic Fibrosis Conference, edited by D.Lawson, p. 225. Cystic Fibrosis Research Trust,Stuart House, London.

May, C. D. and Lowe, C. U. (1949). Fibrosis of thepancreas in infants and children. An illustratedreview of certain clinical features with specialemphasis on the pulmonary and cardiac aspects.Journal of Pediatrics, 34, 663.

Mearns, M. B., Hunt, G. H., and Rushworth, R.(1972). Bacterial flora of the respiratory tract inpatients with cystic fibrosis, 1950-1971. Archivesof Diseases of Childhood, 47, 902.

Millard, F. J. C. (1965). The development and electro-cardiographic diagnosis of right ventricular hyper-trophy in chronic lung disease. M.D. thesis,University of London.

Recavarren, S. and Arias-Stella, J. (1964). Growth anddevelopment of the ventricular myocardium frombirth to adult life. British Heart Journal, 26, 187.

Royce, S. W. (1951). Cor pulmonale in infancy andearly childhood. Report on 34 patients withspecial reference to the occurrence of pulmonaryheart disease in cystic fibrosis of the pancreas.Pediatrics, 8, 255.

Schwachman, H. and Kulczycki, L. L. (1958). Long-term study of 105 patients with cystic fibrosis.Studies made over a five- to fourteen-year period.American Journal of Diseases of Childhood,96, 6.

Shinebourne, E. and Howarth, S. G. (1973). Congenitalheart disease with special reference to the firstyear of life. Medicine, No. 16, p. 999. Publishedby Medical Education (International) Ltd., 3Fitzroy Square, London.

Siassi, B., Moss, A. J., and Dooley, R. R. (1971).Clinical recognition of cor pulmonale in cysticfibrosis. Journal of Pediatrics, 78, 794.

Simon, G., Reid, L., Tanner, J. M., Goldstein, H., andBenjamin, B. (1972). Growth of radiologicallydetermined heart diameter, lung width, and lunglength from 5-19 years, with standards for clinicaluse. Archives of Diseases in Childhood, 47, 373.

Symchych, P. S. (1971). Pulmonary hypertension incystic fibrosis. A descriptive and morphometricanalysis of the pulmonary vasculature. Archivesof Pathology, 92, 409.

Tanner, J. M., Whitehouse, R. H., and Takaishi, M.(1966). Standards from birth to maturity forheight, weight, height velocity, and weightvelocity; British children, 1965. Part I. Archivesof Diseases in Childhood, 14, 454.

Weibel, E. R. and Gomez, D. M. (1962). A principlefor counting tissue structures on random sections.Journal of Applied Physiology, 17, 343.

Wigglesworth, F. W. (1946). Fibrocystic disease of thepancreas. American Journal of Medical Science,212, 351.

World Health Organization (1961). Chronic Cor Pul-monale. Technical Report Series No. 213, p. 6.WHO, Geneva.

Requests for reprints to: Professor Lynne Reid,Department of Experimental Pathology, Cardio-thoracic Institute, Brompton Hospital, London SW3.

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