ENDOCARDIAL FIBRO-ELASTOSIS

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ARTICLES

ENDOCARDIAL

FIBRO-ELASTOSIS

I. Endocardial

Fibro-elastosis

Associated

with

Congenital

Malformations

of the

Heart

By Dorothy

H.

Andersen,

M.D.,

and Janice Kelly, M.D.

l)epartnu’nt.s’ of Pathology and Pediatrie.s, College of Physicians- 00(1 Surgeons.

Cohunbia U1I ivcr.s’iti/, and the Babies’ hospital

(Submitted February 9, accepted June 4, 1956.)

ADDRESS: (I).1l.A.) 622 West 168th Street, New York :32, New ‘tork.

513

Ped

kit

rics

VOLUME 18 OCTOBER 1956 NUMBER 4

F

tBROStS afl(l elastic tissue Pro1ifer1ti1 Ill

the endocardiuin oCcur in association

with a variety of cardiac lesions, both

con-genital and acquired . Endocardial

thicken-ing is commonly conspicuous in

congeni-tally malformed hearts in infants. For nianv

(leca(les 1)0th the malformation and the

fibrosis were considered the result of

endo-carditis occurring in intrauterine life. No

acceptable evidence of an active

inflamma-tory phase was reported, however, and after

the analytic review of Gross this concept

gave way to the hypothesis that both the

endocardial fibrosis and the malformations

were due to abnormal development at the

embryonic stage. The fairly large group

of cases with marked endocardial

thicken-ing but without malformations of the valves,

vessels or septa, has been considered h

most authors as a subdivision of the general

group of congenital malformations of the

heart.

The occurrence of two familial instances

of endocardial fibro-elastosis and the

re-cent reports of similar cases4 have

stimu-lateci LIS to review the cases of congenital

heart disease iii the )athologv files of the

Babies Hospital with respect to endocardial

fibro-elastosis. It became apparent that the

cases of endocardial fibro-elastosis without

associated malformations presented a fairly

uniform clinical as ell as pathologic

l)ic-ture, while the cases of endocardial fibrosis

1SS0ChLt(’(l \Vith con g(’II itt 1 malformations

were far more heterogeneous, with wide

variations in the site and degree of

endo-car(lia I changes. It seemed a reasonable

possibility that the ‘endocardial fibrosis in

the latter group might be Secon(larv to the

malformation and caused

by

abnormal

lres-sures or currents in the flow of intracardiac

blood, in a manner analogous to the endo

cardial thickening and pocket formation

seen in the aortic-outflow tract in aortic

insufficiency. The present investigation was

undertaken to test this hypothesis. A

con-sistent pattern in the en(locar(lial changes

present in all examples of the same

malfor-mation, and a rational relationship to the

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van-17 173 1 1 1 2 1

.514

ANDERSEN

- ENI)OCARI)IAL FIBRO-ELASTOSIS

Otis malformations would be observations

in support of this concept. If such a

rela-tionship were established in the majority of

cases, the converse procedure, that of

mak-ing deductions concerning the direction of

i ntracardiac currents from the observed

sites of endocardial thickening, might he

of valise. Also, the cases of congenital

en-docardial fibro-elastosis associated with

major congenital cardiac malformations

could reasonal)ly 1)e separated from the

cases of congenital endocardial

fibro-elasto-sis without associated malformation, thus

permitting a clearer delineation of the latter

group of cases.

MATERIAL AND PROCEDURE

All cases of major congenital heart disease in

the Babies Hospital necropsv files in the 20-year

period ending in June, 1955, were reviewed

svith the primary Ol)jeCt of evaluating

endo-cardial thickening. In this period, 237 cases of

major congenital heart disease were observed

with an age range from birth to 1:3 ‘ears. One

hundred ninety-nine gross specimens of hearts

from these cases were available for analysis of

eiidocardial thickening. The’ were reviewed in

consecutive order according to date of

nec-ropsv. Heart chambers and atnioventricular

valves were graded 0 to 4 + for degree of

eiiclocardial thickening, 4+ representing the

extreme degree of thickening seen. Sites of

localized thickening in individual chambers

sere noted as svell as diffuse thickening. The

t\’1)(’ of heart disease or congenital

malforma-tion was purposely not observed at the time

of grading. Two independent observers graded

the specimens. Results were then compared,

and where any discrepancy in evaluation

ex-isted in a chamber or valve, the two ol)servers

theti reviewed the specimen together in order

to arrive at the most probable answer. Grading

was over 90 concordant for both left ventricle

and right ventricle. There was less consistent

agreement in evaluation of degree of

thicken-ing of the right auricle, with concordance in

about 75 of cases. Grading of the degree of

thickening of the

left

auricle was unsatisfactory,

with not more than 50 concordance. The

naturally thicker endocardium of the left

auri-cle, and the marked variations of endocardial

thickening in this chamber with age, were

fac-tors 1)robablv res1)onsible for the lack of

coit-formity. Almost identical estimates were

ob-tamed of the degree of mitral valve and

tn-cuspid valve thickening. Thickening of the

pul-monarv and aortic valves was not evaluated.

After all hearts were graded, the neropv

Pro-tocols were reviewed and the diagnosis of each

case noted. The 199 hearts available for

analv-sis formed the following groups:

Congenital endocardial fibro-elastosis,

primarily of the left ventricle

Congenital malformations of the heart

Glvcogen storage disease of the heart

Congenital calcification of the coronary

arteries

Gargovlism with nodular valves

Endocardial fibno-elastosis with

pni-mary nodular valvular involvement (“fetal

endocarditis”)

Endocardial fibro-elastosis with

cham-her other than the left ventricle

pni-manly involved

Total 199

The present study is concerned with the 176

cases of major congenital malformation of the

heart. After completion of the examination of

the hearts, the protocols were reviewed for the

diagnoses, aix! the cases were then classified

according to the major malformation or group

of malformations as determined at the time of

necropsv. Cases with the same malformation

were then arranged according to age at death

(Tables A to C). In a large number, the

corn-bination of malformations occurred in only a

single instance on was considered too

com-plex for analysis, and these cases were omitted

from the stud. There remained 129 examples

of relatively well-recognized malformations.

These cases form the l)asis of the present

re-port. The groups were divided into those

show-ing predomitiaitly right-sided endocardial

thickening, those showing predominantly

left-sided thickening and those showing no

pre-dominance of thickening on either side. Patency

of the foramen ovale, of the atnial septum and

of the ductus arteniosus were checked in all

cases.

Microscopic sections stained with

hemo-toxvlin and eosin were studied in all cases. A

\Veigert elastic tissue stain was also made in

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515

GENERAL

OBSERVATIONS

ON

ENDO-CARDIAL FIBRO-ELASTOSIS

IN

CON-GENITAL

MALFORMATIONS

OF

THE

HEART

Inspection of Tables A to C permits four

general conclusions:

1. Endocardial fibrosis is found in the

iiiajonit’v of cases of con gen ital

inalfornia-tioii of the heart.

:2. Distribution of the sites of endocardial

thickeni ng follows the same general pattenti

in various exanlI)Ies of the same defect.

3. After comparison of the site of fibrosis

with thw 1)ro1a11e current of flow of

intra-cardiac 1)100(1 in each anomaly, it is seen

that fibrosis occurs where local or general

increased pressttre may l)e I)nestltnei to

occur.

4. The degree of fibrosis as a rule

in-Cr(ts(t5 with age in each group. It would

seen-i reasonable to conclude that the

endo-can(hial fibrosis is )rogre5sive and is

secofldi-any to the al)norrnalities ill 1)100(1 flov

cause(i by the nialforinations.

ANALYSIS OF SITES OF ENDOCARDIAL

THICKENING

IN

CERTAIN

TYPES

OF

CONGENITAL

MALFORMATIONS

OF

THE

HEART

The results of the observations are

re-corded

in Tables A

to C and Figure 1.

Com-ments on the mechanism of pro(iuctioti of

the various sites are Preselitecl. A complete

review of the literature on intracardiac

1)100(1 How in the various malformations is

not attempted.

A. Right

Ventricular Involvement

Predomi-nant with Ventricular Septal Defect

I. Uncomplicated Ventricular Septal

Defect (16 Cases)

In all infants over 2 months of age,

local-ized fibrosis was found on the right

ventric-tilar wall in the region of the conus which

lies opposite the defect. Thickening of the

left surface of the septum was first seen at

:smonths

and was presetit in one of two

5-month-old infants and in all older ones. In

the older cases, moderate fibrosis was

oh-5(’Ive(i througlu)nt 1)OthI right auricle dII(l

ventricle. The two oldest 1)ttie1it5, aged 1

and 3 years, both had soie endocardial

thickening of all chaml)ers. In general the

thicksiess of the endocardiuni in the specific

sites and the extent of the involved

endo-cardlium increases with age.

A 1te11t ventricular septuni appears to

l)roiuIce a jet effect in the flos’ of 1)100(1

from the left to the right ventricle which

has its impact on the wall of the right

veti-tnicle directly opposite the defect. The

edges of the septal (iefect, especially the

left aspect, may he set in vibration by eddy

currents.

A high incidence of associated

extracar-(liac malformations was observe(1 in this

group. Only 4 of the 16 cases had no other

major anomaly. The malformations were

varied; those which recurred were

inongol-ism (four cases), vascular ring (two cases)

aIi(i tracheo-esophageal fistula (two eases).

II and Ill. Ventricular Septal Defect and

Coarctation of the Aorta (5 Cases)

In the few cases presented, the 1)attern

resembled that in the uncomplicated

‘en-tricular septal defect. In the hearts with

as-sociated infantile coarctation , general

left-sided thickening ‘as observed at a

some-what earlier age than in any case with

tin-complicated ventricular septal defect. This

may he interpreted as a result of increased

iiressitre in the left ventricle.

IV. Ventricular Septal Defect and Mitral

Stenosis (2 Cases)

In both cases the pattern in the right

heart resembled that in uncomplicated

P1te1it ventricular septum, while the left

ventricle showed more fibrosis for the age

than in the uncomplicated defect. No

e-planation for this is offered.

V. Eisenmenger’s Complex (8 Cases)

The pattenui of endocarclial fibro-elastosis

was similar to that in simple ventricular

septal defect, with thickening of the

endo-cardlium in the conus area opposite the

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(19)

1 2 If

5 6 .7 8

I’I(. I. Sit of (‘ndo(’ardial fll)rosis in reprcsentativ( (‘lS(S of various (OflgtIlital (‘ar(liac irlalforinatiotis.

i’h6”

fibrosis is i’epreseiited

b’

truss-hatching.

I

,

Case :3 1. Eisciuuenger’s c’oinpk’x.

2, Case

49.

I(’tra(l s’’ith (‘011115 StF1IlOSis.

:3, Ctst’ (if). Pulnonk’ (Ftresia.

4, CFS( 75. Total P1hhb0ICFrY seIlOLIS r6’tLlrn to right auricle.

5, Cast 79. Tnt-F ISl)i(l atrcsia with puliiionic stenosis and patent intt’rventriciilar septum

6, Case 94. Ostitini atrio-ventriculare commune \Vitlm siflgl( atrioventricular valve,

7. CaSe I OS, Coart’tation with closet1 titictus artt’riosus; ‘a(ltIlt tV1)(’. ARTICLES

S. CaSt 99. ,Aortic atresia 111(1 niitral stenosis.

1)r’t this fiuiding as an indication that the

shunt is for the most Ptrt from left to right

through the defect. Review of the charts

revealed in most C1S(’S a history of

interniit-t(11t C”s’aliOSiS vith exertion or )u1lmo1i1ry

infection , conipatible with teml)orar\-’

right-to-left shunt.

Tlu’ iiic’reased in the I)tmhm1i1i1rY

artery i-nay be conceived of as a result of

the increase(l l)1(’55th1 fl the right ventricle;

if tliis i nterpretation lx’ correct the changes

in the intra)u1InOflar arterioles vhich have

been rel)orted niav l)e the result rather

than the cause of the pumlmnomiary

h’perten-sion. This concept functionally relates

El-sen nienger. complex vi th ventricular

septal (lefect rather than with tetrad of’

Fallot.

Four of the cases had a major

malfornia-hon t’.1sevhere than in the heart. In two

this was a tracheo-esophageal fistula. The

associated malformation was adequate

cx-planation for the three neonatal deaths.

VI. Eisenmenger’s Complex and Infantile

Coarctation (2 Cases)

This combination occurred in one case

vitl-i neonatal death and in an infant with

true lienm’na1)hroditisni dying at 14 months

o)f age. In the latter case there ‘as

en(io-cardial thickening of all chanibers, uio)st

marked in the left ventricle, which

pnestmmn-ably had increased pressure because of the

coarctation.

VII. Eisenmenger’s Complex and

Auricular Septal Defect (2 Cases)

\larked thickening of the right auricle

and nioderate thickening of the right

(20)

532 ANI)ERSEN - ENDOCARI)IAL FIBRO-ELASTOSIS

this combined defect. In the older child the

tricuspid valve was also markedly

thick-cued.

VIII. Tetrad of Fallot with Pulmonary

Valvular Stenosis (8 Cases)

Fibrosis

of the en(locardiuni is found in

the lower coiiums region Ol)l)O)site the SeI)tal

defect. Cardiac catheterization in cases of

tetra(1 has also shown an increase in the

oxgemi contemit of the right ventricular

sanhl)les ‘.15 compared with those froni the

right auricle and vena ca-’a. C On the other

hafl(l, the clinical cvaiiosis correlates vith

the direct anatomic 1)athwav froin the right

ventricle into) the overri(iing ao)rta. These

co)nfiicting observations max’ l)e harrnonize(l

bV conceiving of the directio)n of flow

thro)nghi the defect as a \‘anial)le one.

lx. Tetrad with Conus Stenosis

(14 Cases)

Although the results of a jet effect on the

right ventricular wall were seen with

valvu-Ian stenosis, they were not ‘.tpp1rent iii

conus stem)Sis . The marked thickening of

the COlitiS en(locardiumn al)Ove the stenosis

may reasonably IW attribute(I to a jet effect

coniparal)le to that wliich I)r0d1u1ce5

post-stCIiOti C (lilatltiO)Ii O)f the psi lmnonary artery

dl)O)\’e a 1)ulIiiOniC valvular stenosis. No

ready explanatio)n is offered for the (liffuse

thickening O)f several chambers. It is

possi-1)le that thi(’ P1rti;l umisatumratio)n of the

1)lO)O)(1 which flows through the coronary

arteries contributes to niVo)car(lial amioxia

‘.iiiol to) the (‘.Ii(io)car(lial fibrosis. The extra

vork of the heart \Vitl1 increased cardiac

olitiMit also l(’Cl(l5 tO) increased oxygen

(Ic-lildli(I.

x.

Tetrad with Both Conus and

Valvular Stenosis (6 Cases)

1’lw location o)f fibrosis reseliil)les that in

tetra(1 with comuis sto,miosis alone.

The large yari(’tv all(I often multiple

1)unhl)er ol seriom is 11OI1-(’aIdia(’

mnalfomnia-tiumis in all 1V1)eS (ml t(’tI’L(lS is (‘vi(lent. ()tl

\‘CtS(’LLlFI mflLlh)t’ImhLtR)fls COlt’ sunl(’tini(’s l)1(’s

3 had a right-sided aorta; of 14 cases of

tetrad with conus stenosis, there were none

with right aortic arch alone, but 3 with right-sided aorta; of 6 cases of tetrad with comitis and valvular stenosis there were 2 with a right aortic arch and 1 with a

right-sidledi aorta.

B. Right

Ventricular Involvement Predominant

with Outflow Impediment but without

Ventricular Septal Defect

xl and

XII.

Pure Pulmonic Stenosis

or Atresia (7 Cases)

The right ventricle showed diffuse

endo-cardial thickening and in most cases the

tn-cuspid valve and right auricle were also thickened. This (IistflbutiOn of the fibrosis

niav be interpreted as the result of increased

iresstmre iii the right ventricle, accompanied

by dilatation and incompetence of the

tn-cuspid valve. It is of interest that the

tn-cuspid valve showed thickening in the pres-cut group of cases, hut not in the following

ones, although the right auricle and

ventni-dc were 1)0th affected in both groups. Left

ventricular endocardial fibrosis was

ob-served in the older patients, a finding for

which no explanation is offered.

Other cardiac anomalies and other con-genital malformations were almost totally

absent in this group of cases.

C. Right

Auricular Involvement Predominant

with Dilatation and Increased Pressure in

the Right Auricle

XIII. Total Pulmonary Venous Return

to Right Auricle (5 Cases)

In total pulmonary venous return to the right auricle, the double burden on the

right heart is reflected by dilatation,

hyper-trophy amid fibrosis of the endocardium in

both right auricle and right ventricle. The

mild fibrosis of the left ventricular

endo-cardiurn seen in two of the older infants

may 1)(’ the result of severe anoxia. The

chamiges in the might heart ‘t’re the sanie

\‘h(’ther time lMmlIliOnarv \‘(‘ills entered the

(21)

ARTICLES

In aolditioii to tlI(’ five cases ol tO)t’.Ll

I)tml-nionary \‘eiio)us return 1)res(’mit(’(l in 1’ahle

C there was one with multiple anomnahies

of the heart amid other structures. Four

addi-tional cases iii vhich one or tvo )tmlm1i1i1r

‘(‘i1i5 (‘Iitd’m(’(l the right uiricle amul the

rti’-niainder folloved the normnal course ‘ere

not listed. These all had niultiple anomalies

of the heart and o)ther organs and were

con-sidered to)O CO)liipleX for amialysis . Partial or

total l)t1hm1i1i;1rY venous return to the right

auricle therefore occurred in 1 0 of I 76

cases.

XIV and XV. Tricuspid Atresia

All cases of tricuspid atresia showed

(hf-fuse eml(locardial fibrosis of the right auricle

and also localized fibrosis of the val1 of

the right ventricle opposite the septal

(he-fect. The former may be attributed to a

(hiffusc increase iii iressumre in the right

auni-dc comisequent to obstruction to outflow,

dmi(l the latter to jet effect. The (liffuse right

ventricular fibrosis seen in sonic cases max’

l)c considered as due to increased right

en-tricu lar seco)ndary to the

Pulmn-nary stemiosis usually associated vith this

lesion. The left ventricular fibrosis in the

tWO) eases vith associated transposition is

not uliderstO)Od.

INI ajor aflOmlnalies iii other svstemns ‘ere not observed in this group.

D. Right-sided

Involvement Predominant with

Communication of All Chambers

XVI. Ostium Atrio-ventriculare

Commune (13 Cases)

\-lo(Ierate endocardial thickening was

found in the right auricle and ventricle,

slightly niore marked in the former. Tlwre

\\,as also So)miie thickening of the left aspect

of the ventricular 1)ortion of the defect

simni-lar to that seen imi uimicomphicated

ventnicu-Ian septal defect. The greater right-sided

endocardial thickenimig is in accord with the

view, based on the tramisitorv miature of the

CVamiO)sis and the right axis deviation found

clinically, that the shummit is preclomnimittitly

left to right.

Five instances of flio)ngohism were found

in the 1:3 cases. 1h( Cases vith niommgohismu

shoved a, higher inci(lence of other

nial-formations than those without m’no)ngOl ism.

E. Left Ventricular Involvement Predominant

with Outflow Impediment

XVII to XXI. Left-sided Involvement

Predominant with Outflow Impediment

(14 cases)

This group of cases includes those with

aortic stenosis o)r atresia and those with

c’O)arCtatioli of the aorta. “Infamitile

coarcta-tion” signifies a widely 1)ttemit (luctus

an-teniosus, while a(Iult type” refers to) cases

with a closed (huctims. Imi all hut one (Case

95), the left ventricular emidocarclium

showed diffuse thickenimig varvimig from

mnild to marked in degree, while the right

ventricle was only occasionally affected.

The cases of aortic stenosis and atresia

were free from extracardiac malformations

while those of coarctation showe(I a high

imici(heflce.

F.

Fibrosis due to Local Deficiency in Myo-cardial Blood Supply

XXII. Anomalous Origin of Left Coronary

Artery from the Pulmonary Artery

(3 Cases)

Fibrosis occurred over the (legemierated

area of niyo ardiuni, vhich w’as located iii

the amitenior wall of the left ventricle and

anterior Iortion O)f the vemitnicumlar sptun1,

the region norm’nahlv supplied i)V the

an-tenor l)ranch of the left coromiary artery. It

is amialogous to the fibrosis oven a coro)miar\’

infarct following occlusion o)f the artery

and nee(h not l)e attributed to alterations

of pressure of intracardiac blood.

G.

Cases without Marked Endocardial

Thickening on Either Side

XXIII. Transposition of the Great

Vessels (8 Cases)

Of 28 cases in which this anomaly was

found, 20 showed other complex anomalies.

In the eight cases without other major

(22)

endo-534 ANI)ERSEN - ENDOCARDIAL FIBRO-ELASTOSIS

(,‘Ctr(hiCtl thickening. IlO#{188}’eVe1, this may le

I)trtly’ (tue to) the sho)rt survival tune, the

longest being 5 months.

XXIV. Transposition of the Great Vessels

with Moderate Ventricular Septal

Defect (6 Cases)

The cases O)f cor tniloculare are excluded.

The survival time is longer than in simple

transposition . Endocardhial fibrosis was

mninimal and followed the 1)attern found in

simple ventricular septal (lefect.

XXV. Patent Ductus Arteriosus

Moderate endocardial thickening was

found on 1)0th sides of the heart. It would

seem reasomiable to interpret this as due to

vanial)le directiomi of flow through the

duc-tus, placing intenm’nittent strain on both

vemitricles.

MICROSCOPIC

OBSERVATIONS

The emldocan(hial fibrosis consists of a

thick layer of collagenoums and elastic

tis-sue fibers hetweemi the emidocandium an(I

the mnuscle, often w’ith some extensions into

the latter. Just beneath the endocardium’n

both types of fibers tend to be finer than

are those nearer the mtmscle. Because the

iresence of elastic fibers has assumed

prom-inence in the literature, ‘Weigert elastic

tis-sue strains were performed in 35 cases,

rep-resenting all types of malformations. With

OflC exception, all cases graded as having

:3+- or 4+ endocardial thickening were

in-chided. Elastic tissue was found to

accom-pany the collagen fibers in all cases. A

con-trol group of seven cases of vanious types

with endocardial thickening was similarly

studied. These imicluoiled cases of rheumatic

heart disease, glcogen disease of the heart,

chronic glomertmlonephnitis amid polycystic

kidmieys. Elastic fibers were found to

accom-pami collagemi fibers in the thickened

endo-cardiuni ii’i all instances.

On the I)aSi5 of this evidence it was

con-eluded that both elastic fibers and collagemi

fibers partake imi the fibrosis of the

endo-cardium from a variety of causes. Elastic

tissue proliferation is not a distinguishing

feature of elmolo)c’arohial fibrosis associat(’(l

‘ith comigemi ital nia lformuations o)f the heart.

Endocardial fibro-elastosis i s therefore

analogous to cirrhosis of the liver iCi that

milicroscopic Sttmdly of the end result often

fails to reveal the pnim’narv cause of the

fi-brosis.

MECHANISM OF PRODUCTION OF

ENDO-CARDIAL FIBRO-ELASTOSIS IN

CON-GENITAL MALFORMATIONS OF

THE

HEART

Endocardial fibrosis occurs in a variety of

diseases, sometimes without well

under-stood cause. In the group of cases under

investigation, mechanical factors probably

play an important hut not exclusive role iii

its production:

1. The foregoing data present evidence

that a prolonged increase of intracardiac

blood pressure is consistently asso)ciated

with fibrosis and may be interpreted as a

cause for it. Marked localized fibrosis, as

in the right ventricle opposite a p1tency of

the septum, may result from a “jet effect.”

2. Vibration may reasonably he assumed

to be traumatic. The thickemied tricuspid

valve found in pure pulmomiic stenosis may

be due to vibration caused by regurgitation

through the valve. It is suggested that the

thickemiing over the left aspect of the

sep-tumi’i surrounding a ventricular defect may

l)e due to vibration fromn ed(IV currents.

3. Low oxygen saturation of the arterial

blood supplying the myocardium is

prob-ably an important factor in the production

of endocardial fibrosis. Johnson5 has given

strong support to this concept. The role of

amioxia is obvious in the fibrosis of the entire

wall in the area supplied

by

a coronary

artery arising from the pulmonary’ artery.

Partial anoxia probably contributes to the

fibrosis in a variety of types of cyamiotic

heart disease. The frequent occurrence of

areas of myocardial fibrosis and calcification

as well as endocardial fibro-elastosis in

cases of aortic atresia may he interpreted

as partly the result of especially severe

anoxia, as the mixed blood reaches the

(23)

ARTICI ES 535

Ct1teIiO51Fs amm(l r(’trO)gra(le fh)\” (lo\’Im the

ascemxling aorta, probably umider low

pres-sure. In mamiv malformations the excess

vork required of the m’nyocardium under

the hami(hicap of a miialformned heart

pne-sumnablv increases the (lemnand for oxygen

afl(l sensitivity to) the lack of it. Because the

emidocardium is the last portion of the heart

‘all to l)e reached by blood from the

coronarv arteries, this mnav l)e comisidered to

l)e the area least well supplied.

The share of damage to the endocardium

cOfltnil)uted l)\’ partial anoxia and by

me-chanical factors must vary videly from case

to CLSe an(l ill differemit areas in the same

heart. Together these two factors provide

a reaso)nable explanation for most of the

emidocar(lial fibrosis seen in congenitally

miialformned hearts.

There is mio good evidence that either

in-k’c’tiomi o)r (lietarv insufficiency is a conimomi

direct cause of endocardial fibrosis in

con-genital heart disease, though both are

in-cnimninate(I in) certain ty1)es of endocardial

thickemiing. The cases of comigemiital heart

(lisease following rubella of the mother

dur-ing eanl’ pregnancy have resulted in varied

mrtalformations \‘itho)ut conspicuous

emidlo-cardial fibrosis. No other type of infection

has 50) fan l)eemi proven to he imrmphicated in

the etiology of congemiital malformations of

the heart.

-REVIEW OF THE LITERATURE

Approximiiatelv 100 cases of endocardial

fibrosis associated with congenital

malfor-mations of the heart have been collected

from the literature. ‘ :I They are commonly

rel)orted together with cases of endocardial

thickening of o)ther types, of which the most

cO)Ii’IOiOfl are the cases associated with

inter-stitial nivocarditis and the cases in which no

associated lesions of any sort are

demon-strable. This variation in case material has

l(’(l to cO)mifusiOmi in discussions of etiology.

The fol lowing discussion al)pliesspecifically

to the cases with associated cardiac

malfor-inations.

Analysis of the types of malformations in

the cases reported as instances of

endo-cam(hial fibro-elastosis shOVVs that mnLmmv

formations are represented!. The site and

degree of endocardial fibrosis have been

compared with those iii the presemit cases

afl(l have been found to be similar for like

malformations. Aortic stenosis on atresia

with endocardial fibrosis of a small left

ventricle was I)reseflt in slightly mnore than

half of the reported cases. This was

associ-ated with mitral stenosis or hvpoplasia and

with warty vegetations on the aortic or

m’nitral valve in many instances. The second

lesion in the frequency was coarctation of

the aorta of either the infantile or adult

ty)e with left ventricular thickening. The

third lesion occurring in a significant pro-portion of cases was pulmonic stenosis or

atresia with endocardial fibrosis of the night ventricle. These cases have in common ami

obstruction of the outflow tract of a

yen-tnicle. Together the’ account for

80

of the cases recorded as endocardial

fibro-elastosis associated w’ith congenital

mnalfor-mations of the heart. The majority, about

two-thirds, of the neponte(l cases of aontic

stenosis on atresia were in Patiemits who (lied

under 2 weeks of age, and most of the

re-mainder as well as most cases of pmmlmonic

obstruction were fotmiid in infants who died

before the age of 6 months. Patients with

coarctation had as a rule a longer life span.

The hypotheses which have been sug-gested for the etiology of endocardial

fibro-sis associated with congenital cardiac

mal-formations are:

1) Infection was tramismitted from the

m’nothen during intrauterine life.

2) The endocardial thickening represents a malformation . 1. C

3) The endocandial thickening is

fumic-tional in origin and secondary to alterations

in blood! flow.1

4) It is the result of anoxia.5

Although the first three of these

hvpothe-ses were suggested by earlier authors, the

(24)

care-536 ANDERSEN - ENDOCARDIAL FIBRO-ELASTOS1S

Imilstuds’

III sll)port O)f this lw’pothesis is

that o)f Craig. ‘ Tho’ pr’s’t stu(h’ 1)rO\’ides

evidence in suI)I)Ort of a functional origimi

O)f the endlOcar(hial thickemiing in the

major-ity O)f cases.

ENDOCARDIAL FIBROSIS IN THE

NEONATAL PERIOD

Iii iiio)st tVI)es of con genital inalfoninations

O)f the heart the en(lo)c’ar(hium shows hut

little fibrosis in those cases comning to

necropsv in the first milo)nth or t\v() of life.

Tlwre are, luwvever, several groups of cases,

those with l)tilmiiomiic atresia (Group XII),

those with aortic atresia (Group XIX) and

those with severe aortic and mitral stenosis

(Group XVIII) in which maximal

endo-car(hial fibro-elastosis is Presemit at or near

birth. Because in these cases the

endo-cardial fibrosis occurs dunimig intrauterine

life, amid as death occurs in the neonatal

penio(I, it is not 1)055i1)le to demonstrate a

)ro)gressive imicnease in the fibrosis with age.

However, the statement that the location

of fibrosis follows the samne I)1ttenn in

dif-fenemit exanil)les o)f the same defect remains

valid. If the hy’pothesis o)f the functional

origin O)f en(locar(lial fibrosis is true for

those cases where the thickenimig is minimal

in the neo)natal I)enioi but increases with

age, it miiav i)e true for these cases also. If

it is not, we are forced to) consider them as

a separate etiological group, which seem’ns

improbable.

The mnajonitv of comigenital cardiac

trial-forniationis seen at miecropsy are of a nature

to I)ermit satisfactory circulation during

fetal life. Presumably those which do not

have led to death of the fettms in the first

half of’ )regnancv. Eisen niemiger’s complex,

total )ulmonary venous retimrn, and

infan-tile coarctatiom’i of the aorta with patent

(luctus, to give a few examples, provide no

hamidhica1) to the infamit in utero. However,

atresia O)f either the pmmlmomiic o)n aortic

‘Ctlve with )atenc of the corresponding

atnioventnictmlan valve results in a chamber

with ingress hut no egress, and can be

con-ceived as resulting in excessive systolic

1)100(1 to reach the coronary orifices in

aortic atresia and severe aontic stenO)sis and

the evidence of myocardial anoxia provided

by focal fibrosis and calcification in the left

ventricle in these cases have been

men-tiOiie(I.

Warty nodular thickening of one or more

of the valves occurs in some of these cases

and for this reason many have been

re-1)Onte(I as fetal endocanditis. In the present

series wartv nodules were found in the

valves in 10. cases: Cases 95, 97, 98, and

7 others with complex anom’nalies.

Histo-logically the nodules are composed of fetal

connective tissue with an irregular an-iangement of fibrocytes traversing a

myx-omatous matrix, without leukocytic

re-spouse.1 Recent authors have considered them as malformations arising from

abnor-mal valvular anlagen.

It is possible, however, to conceive that the complex circumstance of mechanical trauma acting from early intrauterine life on fetal endocardium which suffers from partial anoxia may produce greaten prolif-eration of the valvular tissues than that

vhich follows the action of trauma and

anoxia on more mature tissue.

Evaluation of this hypothesis by

expeni-mental embryologic methods may he possi-ble. The factor of anoxia is of importance,

as no cases of coanctation of the aorta with

a normal ao)rtic valve, and no cases of

moderate aortic stenosis with a large left

ventricle and post-stenotic dilatation of the

aorta have been found in which warty veg-etations were described; arterial blood is supplied to the coronary arteries in these malformations. Most but not all of the cases showing wanty nodules were those of severe aortic stenosis and a hypoplastic left

yen-tnicle. However, mural endocardial

thick-ening is found with all types of severe oh-struction of the aortic valve or aorta.

SUMMARY AND CONCLUSIONS

The site and degree of endocardial

fibro-sis has been estimated and recorded in 129

(25)

con-ARTICLES

Mechamiical factors, imicludimig increased

pressure and abnormal currents of intra-cardiac blood, are of importance in the pro-duction of endocandial fibrosis, because the

sites of fibrosis follow the same pattern in

various examples O)f the same defect and

occur where general imicrease in intracardiac

iressure max’ l)e 1)restmmedl to occur on where localized! jets may impinge on cause

vibration. The degree of fibrosis increases

with age.

Deficiency o)f o)xygemi in the cono)nary l)lOo)(l supply is also of importance, espe-cially imi cases of severe aortic stenosis on atresia and in hearts vith a coronary artery

arising from the )ulmonary artery.

A hypothesis is offered that the warty

valvular vegetations o)ccaSiomially seemi with

aortic stenoss rel)resent the reaction of

fetal valvular endocandium to mechanical

factors combined with hypoxia.

Elastic tisstme stains show that

prohifera-tion of elastic fibers occurs in association

with proliferation of the collagen in the thickened endocardium found in congeni-tally malformed hearts amid in other types of

heart disease. It is concluded that elastic

tissue is a normal co)m’nponent of endocandial

fibrosis.

REFERENCES

1. Gross, P.: Concept of fetal endocarditis;

a general review with report of an

illustrative case. Arch. Path., 31 :163,

1941.

2. Craig,

J.

\I. : Congenital endocardial

scle-rosis. Internat. A. M. \-luseums Bull.,

30:15,1949.

3. Oppenheimer, E. H. : The associatiomi of

a(lUlt-t\’l)e coarctation of the aorta with

endocardial fibroelastosis in infancy.

Bull. Johns Hopkins Hosp., 93:309,

1953.

4. Ullrich, 0. : Angeborene Herzhvpertrophie

mit endokardfibrose bei zwei eineiigen

Partnern von m#{228}nmilichen Drilhingen.

Ztschr. menschl. \‘ererb. u.

Konstitu-tionslehre, 21 :585, 1938.

5. Dordick,

J.

I.: Diffuse endocardial fibrosis

audi cardiac hvpertrophv in infancy :

re-port of two cases in consecutive siblings.

Am. j. Chin. Path., 21:74:3, 1951.

6. Rosahn, P. D.: Endocardial fibroelastosis;

01(1 and new concepts. Bull. New York

Acad. Med., 31:453, 1955.

7. Bing, H.

J.,

Vandam, L. D., and Gray,

F. D., Jr. : Physiological studies in

con-gemiital heart disease. III. results

oh-tamed iii five cases of Eisenmenger’s

complex. Bull. Johns Hopkins Hosp.,

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SUMMARIO IN INTERLINGUA

Fibro-Elastosis

Endocardiac

I. Fibro-Elastosis

Endocardiac

Associate

con

Congenite

Malformationes

del

Corde

Le occurrentia die duo casos familial de

fibro-elastosis endocardiac e recente reportos

die simile casos ha occasionate un examination

(id CaSO5 de congenite morbo cardiac in le

arcliivo)s de pathologia de Babies Hospital de

New York a fin die studiar Ic altere casos de

fibro-elastosis endocardiac 11 deveniva

appa-rente que Ic casos die fibro-elastosis endocardiac

Sill! associate malformationes presentava Un

pic-tuna clinic e pathologic que esseva satis

uni-forme, durante que le casos de fibrosis

en-docardiac associate cmi malformationes

con-genite esseva multo plus heterogenee, con multe

variationes in he sito e le grado de

cambia-mentos endocardiac. Il pareva plausibile (f tie

he fibrosis endocardiac in Ic secunde grupo

esseva secundari al malformation e esseva

causate per anormal pressiones o currentes in

le fluxo de sanguimie intracardiac dc tin maniera

amialoge al spissamento endocardiac e al

forma-tion de tascas (lt1C se manifesta in Ic tracto de

effluxo aortic in casos dIe insufficientia aortic. Le presente investigatiomi esseva interprendite

pro probar iste hvpothese.

In 129 cordes con relativemente simple

nial-formationes congenite, he sito e grado de fibrosis

endocardiac esseva estimate e registrate. Le

grande majoritate de iste cordes monstrava

spissamemito endocardiac.

Factores mechanic ltme inckmde pression

aug-mnentate e anormal currentes intracardiac die

sanguine es importante in Ic production de

fibrosis endocardiac, proque in vane casos del

mesme defectos he sitos de fibrosis ha Ic mesme

distribution, occurrente ubi umi augmento

ge-neral in he pressiomi cardiac pote expectar se o

ubi impulsos localisate de sanguine pote

im-pinger 0 causar vibrationes. Le grado die fibrosis

cresce secundo le etate.

Deficientia de oxygeno in he sanguine

coro-nan es etiam importante, specialmemite in casos

de sever stenosis aortic o de atresia e in cordes

con tin arteria coronari nascente del arteria

pulmonar.

Le hvpothese es avantiate que le

vegeta-tiones verrucose valvular que a vices es vidite

in casos de stenosis aortic representa le reaction

de fetal endocardio valvular a factores

me-chanic in combination con hypoxia.

Preparatos del texito elastic demonstra que

proliferation del fibros elastic occurre associate

con proliferation del collageno in Ic spissate

endocardio que es trovate in congenite

malfor-mationes del corde e in altene typos dc morbo

cardiac. Nos conclude que texito elastic es tin

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