Clinic al communications

Scarring of the pap.iIlary muscles

in left ventricular hypertrophy

Ernest0 Arosemena, M.D. James H. Moller, M.D. Jesse E. Edwards, M.D.

Minneapolis and St. Paul, 1Mkn

F ibrosis of the left ventricular papil- lary muscles in infants and children

with anomalous left coronary artery’ and in infants with congenital aortic valvular stenosis2 has been described in communi- cations from our institutions. One of the consequences of fibrosis of the papillary muscles is mitral insufficiency. The present work is an extension of the study on papil- lary muscles to other cardiac conditions associated with left ventricular hyper- trophy. The material investigated was from infants, children, and adult patients with the following conditions: aortic valvu- lar stenosis, coarctation of the aorta, endocardial fibroelastosis, and left ven- tricular hypertrophy with failure, either idiopathic in type or the result of hyper- tension. Since coronary arterial disease may cause fibrosis of the papillary mus- cles3 cases with more than minimal coro- nary atherosclerosis were not included in the study.

In each of the conditions studied, a greater degree of fibrosis was present in the left ventricular papillary muscles than in control hearts, and the severity of fibrosis of the papillary muscle could be

correlated with angiographic evidence of mitral regurgitation.

Material and methods

Eighty-four diseased hearts from the Cardiovascular Registry of The Charles T. Miller Hospital were reviewed. Among the 45 hearts from children or infants, there were 12 cases of aortic valvular stenosis, 10 cases of primary endocardial fibro- elastosis, and 23 cases of coarctation of the aorta.

Of the 39 specimens from adults, there were 22 examples of isolated aortic valvu- lar stenosis, 5 of coarctation of the aorta, 2 of endocardial fibroelastosis, and 10 of left ventricular hypertrophy with cardiac failure. In 7 of the latter 10 cases, systemic hypertension had been present, the re- maining 4 being examples of idiopathic hypertrophy. In no case was coronary atherosclerosis of more than minimal degree present. In each case the chordae tendineae of the mitral valve were normal. The valvular leaflets, except for “rolling” of the free edges in some cases secondary to mitral insufficiency, were likewise intrinsically normal.

From the Departments of Medicine, Pediatrics, and Pathology, University of Minnesotn, Minneapolis. Minn., and the Department of Pathology, The Charles T. Miller Hospital, St. Paul. Minn.

This investigation was supported by Public Health Service Research Grant 5 ROl HE-05694 and Research Training Grant 5 Tl HE 5570, from the National Heart Institute.

Read before the .4nnual Meeting of the American Heart .4ssociation, New York, N. Y.. Oct. 21 to 23. 1966.

Oilier than the group with coarctation oi i-he aorta, coexistent congenital cardiac malformations were not present. Among :Ile su!)jects with coarctation of the aorta, t!lere were 2 in which this condition oc- wrred as an isolated malformation. In the remaining cases the associated mal- formations were ventricular septal defect (7), atria1 septal defect (5), patent ductus iirteriosus (4)) patent ductus arteriosus and ventricular septal defect (3), aortic valvular stenosis (a), and 3 with other :ualformations.

In addition to the 84 specimens with

cardiac dk~~, 13 lierili,;.: ‘:c;, et-: r\ ~‘1 e studied as controis. These wert: tircili! pa- tients ranging in age from 25 d;iy~ to 68 ?ears, corresponding to the age range ;,i *he si;bjects with cardiac disease.

%?th one exception,* from eaci? speci- :iien 5 areas were sampled io- i1islologic study. These were: (1) the aate Eor papil- ‘ary muscle of the right ventricle (J\F’.\I RZ’) ~ :2) the left ventricular \i.all at tl!e :~ase of :ke left ventricular anterior papii!ar>- mus-

Pig. 1. l’hotomicrographs of left ventricular papillar), ?nuscles and adjace,lr oortioris d i&c L\ !,i kiik: \rd;i i-0 show the criteria for the various grades of fibrosis designated. (Each stained for elastic t& e; each >< 1.) a, Norma! papillary muscle. b, Grade 1. Interstitial fibrosis minimai (usually requires higher nlr:gnification for ;dentification). c, Grade 2. Small scars and interstitial fibrosis. d, Grade 3. Single conglomerate iirea of fibrosis iinvolvil:g distal third of papillary muscle). e, Grade 4. Multiple conglomerate areas of fib,-os;-( -&), few :e- inaining areas of ml-ocardium. Minimal fibrosis of adjacent left ventriclllar wail.f, Grade 5. Aktrouhir papillarv musck. Extensive fibrosis, involving entire papiky muscle. (Minimal fibrosis of adjaceiil. left ~e~~;r&i;ir w,vai?..)

448 Arosemenct, d%ller, and Edwurds

cle (LVl), (3) the anterior papillary muscle of the left ventricle (APMLV), (4) the posterior papillary muscle of the left ven- tricle (PPMLV), and (5) the left ven- tricular wall at the base of the posterior papillary muscle (LV2). Of the 2 sections prepared from each site, one was stained with hematoxylin and eosin and the other with Lawson’s elastic tissue stain and counterstained with Van Gieson’s connec- tive tissue stain. Sections were reviewed independently by two observers, and the degree of fibrosis present was graded ac- cording to the following criteria (Fig. 1): grade 0, normal muscle; grade 1, occasional small areas of interstitial fibrosis; grade 2, multiple focal scars and small areas of interstitial fibrosis; grade 3, single con- glomerate scars as well as interstitial fibrosis; grade 4, large and multiple con- glomerate areas of scarred myocardium. islands of intact muscle remaining; grade 5, extensive scar, usually with gross atrophy of papillary muscle.

In order to compare the degree of fibrosis in the various sites and conditions, an index of jibrosis was determined in the following manner. For each condition and site, the grade of fibrosis for each case was

added and the sum divided by the total number of cases of that particular con- dition. This yielded an index of fibrosis for that site among all the cases with the condition concerned.

Of the 84 patients included in the study, left ventricular angiograms had been done in 19. These were reviewed for the presence or absence of mitral insufficiency. Using the grades of fibrosis of papillary muscles which had been determined for these cases, an index of fibrosis of the papillary muscles was calculated for those cases with mitral insufficiency and for those with competent mitral valves.

Results

Prevalence of jibrosis. Among the control hearts no fibrosis of papillary muscles was observed in infants or children, but some degree of fibrosis was commonly present in the hearts from adults. This yielded a value of about 30 per cent for some degree of fibrosis of papillary muscles among all the control hearts (Fig. 2). In each disease state, however, the percentage of cases with fibrosis of the papillary muscles of some degree was greater than in the con- trols. The greatest prevalence of fibrosis

FIBROSIS OF L.V. PAPILLARY MUSCLES

(all grades included)

Percent 100 -

go-

ao-

70.

60 -

50

40

30 i

20

10

r Controls Aortic L.V.

Stenosis cordial Hypertrophy I Fibro- with

elastosis Failure

APM L.V.

Es3

,; L,v,

Fig. 2. Prevalence of fibrosis in left ventricular papillary muscles regardless of grade, according to underlying condition.

occurred among patients with aortic vaivu- Tar stenosis. The prevalence of fibrosis in <:oarctation of the aorta and in endocardial *ibroelastosis was less than in the two fore- ;oing conditions but greater than in the control hearts.

To determine changes in the degree of Gurosis which might occur with age, the cases were divided into two categories: hildren and adults. Comparisons were also made of the index of fibrosis in each of the ventricular sites in each of the car- diac conditions. The results of these analy- ses are shown in Figs. 3 and 4.

Irtdex of jibrosis in infants and children (i;;g. 3). Among the control cases of in- iarits and children, fibrosis was not ob- served. In aortic stenosis the index of hbrosis of the left ventricular papillary ihuscles was 4, indicating a severe degree of change, while lesser degrees of fibrosis ivere in the left ventricular wall near the papillary muscles. Fibrosis of papillary muscles was 21~0 present in the patients with coarctation of the aorta and primary endocardial fibroelastosis but was of less

je*eriry rild?il in a0.. tlC 5,t:.!;?* 3) U ii11

:IIarked variation in the grdcies of !it)r~sis

among the cases %ith a particuhi- lesion. 3n several cases of coarctation of : be aorta 1% ith coexistent ventricular or atriril septal defects, the papillary muscles were nornla!. !n the few cases with associated rI$~t ven- tricular hypertrophy, mild fibrcGs was

present in the papillary muscie of the right ventricle.

Index ojJibrosis in adults (AFigs 4;. ,knorrg tile control hearts from adu’l~, ;be index of fibrosis was highest in the j)aoillary muscles of the left ventricle, t!:e Gghest grade of fibrosis observed being 3. In adults aortic valvular stenosis was associnted with the highest index of fibrosis of the papillary muscles. The range of cbrosis in aortic stenosis varied widely among tile cases, with several revealing fibrosis of Grade 4 and 5 in the papillary muscles.

Among adults with coarctation of the aorta, the highest index of fih& was in ihe anterior papillary muscle of the felt ventricle, with a lesser degree at the bases Qf the papillary muscles and the posterior

CHILDREN

j @APMR.v,

ot Fibrosis 36 Not Studied

Range 00000 * ,/42/52’5,,3 /3 /2 x5 ,2 ,I GO000

/2 ~3 ~5 ~5 ,5 OOOGG

Controls Aortic Srenosis Coarctation Endocaid:al Fibroelostosls

No of cases 4 i2 23 IO

CONDITIONS _--_--.._ -

Fig. 3. in mCar,ts and children the index of fibrosis at the various sites studied, according i;o i:~~kr~yirq, ,. J:!- ditions. (Right ventricular papillary muscle not studied ir, aortic stenosis.)

450 Arosemena, MoLLer, clnd Edwards .4wl. Hcwt J. October, 1967

Index of

Fibrosis 5

ADULTS

Controls

No. of cases (7)

Aortic Stenclsis Coarctation Endocardial L.V. Hypertrophy Fibroelastosis )uith Failure

(22) (5) (2) (IO)

CONDITIONS

Fig. 4. In adults the index of fibrosis at the various sites studied, according to underlying conditions.

papillary muscle of the left ventricle. In endocardial fibroelastosis and left ven- tricular hypertrophy with failure, the dis- tribution of fibrosis was similar.

Relation of mitral insuficiency to fibrosis of pa+&ry muscles (Table I). Of the 84 patients in this study from whom speci- mens had been obtained, left ventricular angiography had been performed in 19 as part of the diagnostic study during life. In 15 of these patients mitral regurgitation had been demonstrated. Eight of the 19 patients with left ventricular angiograms were infants, and in each mitral regurgi- tation had been demonstrated. Primary endocardial fibroelastosis was present in 3 and aortic valvular stenosis in the re- maining 5 cases. Of the 11 adult patients so studied, mitral regurgitation had been demonstrated in 7. In the latter, aortic stenosis was present in 6, and coarctation of the aorta was present in the seventh. The average index of fibrosis of the left ventricular papillary muscles in the 1.5 subjects with demonstrated mitral insuf- ficiency was 3.3, while in the 4 patients

with angiocardiographic demonstration of competent mitral valves the average index of fibrosis was 1.5.

Comment

In previous studies on anomalous origin of the left coronary artery from the pul- monary trunk’ and on aortic valvulat stenosis in infants,2 it appeared that each condition was commonly associated with clinical and angiographic evidence of mitral insufficiency. The valvular incompetence was believed to result from infarction with secondary fibrosis of the left ventricular papillary muscles. In patients with anom- alous origin of the left coronary artery from the pulmonary trunk, the infarction is related in part, at least, to the coronary arterial abnormality, while among the infants with aortic valvular stenosis the mechanism was not clear. In another study4 mitral insufficiency was commonly found in infants with primary endocardial fibroelastosis. Structural abnormalities of the papillary muscles were thought to be responsible for the valvular abnormality,

I Mitral insuficiency Concpetent m itial ualve

(7 adults, 8 children) (1 adults)

I .Interioi Posterior Both Anterio; P OStPrioY ~ il’nth

3.4 3.2 3.3 2.1 25 1 I 5 (l-5) (l-5) (l-5) (l-4) (O-2) (, I ~4 !

..- l_l____.___l__

:.)ut histologrc study of the papillary mus- L,les had not been performed. The present study indicates that fibrosis of the left ventricular papillary muscles is commonly iound in this condition. This histologic change may have an important influence in the generation of mitral insufficiency in endocardiai fibroelastosis.

Infarction and fibrosis of papillary mus- c;es is commonly observed among cases of infarction of the left ventricular wall in t!le region of basal attachments of the papillary muscles. YIitral insufficiency has !)een associated with this cl-iange.3s5 It is probable that the mitral insufficiency ob- served in our cases is likewise associated with dysfunction of the papillary muscles resulting from fibrosis.

The fibrosis of papillary muscles noted in our cases is interpreted as resulting from iuyocardial infarction. Indeed, in some of the infants necrotic muscle was found in association with scar tissue. The basis for a tendency to focal infarction of the myo- cardium, and in particular of the papillary znuscles in the several states studied, needs discussion. It is likely that the hyper- Lrophied myocardium increases the re- sistance to perfusion of the myocardial capillaries. The arteries of the papillary inuscles have a greater distance to tra- verse6r7 than do the arteries of the free l?vall of the left ventricle. All other con- ditions being equal, this would appear to xnake the papillary muscles particularly vulnerable to infarction.

The papillary muscles of the left ven- tricle, the related left ventricular wall, and the anterior papillary muscle of the

right ventricle Tvere srudieci :or I/ isrologic. evidence of and extensiveness of fil,rosis. in addition to controls, in seve::~~? condi- tions associated with left ventricular hy,- pertrophy, necropsy specimens of heart \\-ithout significant coronary disease from 84 cases including 45 from infants or chil- dren and 39 from adults with a variety of disease states were studied. ‘i’he con- ditions included aortic stenosis, coarcta- tion of the aorta, endocardial fi!troelastosis7 and left ventricular hypertrop!ly n-ith failure. In none Iv-as coronary athero- sclerosis present.

In each condition studied, tlte degree of fibrosis observed in the left ventricular papillary muscles was greater iilan that observed in contra! hearts. ?‘l!ere :ws direct relationship between stw~=ri tv * ‘I 2 or Sbrosis and the angiographic denionstra- rion of mitral insufficiency.

The common denominator was left ven- iricular hypertrophy which appears re- sponsible for the scarring of the left ven- Lricular papillary muscles. Jlitra; valvular ;nsufficiency may result in chose cases with extensive scarring of the 1~21; ven- tricular papillary muscles

KEFEREKCES

Soren, G. R., Raghib, G., Molier. j. ii., AZI- platz, K., Adams, P., jr., and F:d;~.x&, J, E.: .homalous origin of the left coro:iary artery :rom the pulmonary rrunk with special re:er- ence to the occurrence of mitral i:~s~~%cie~-~, Circulation 30:171, 1964. Llolier, J. H., Nakib, A., and Eri~ards, J. E.: Infarction of papillary muscks and mitral in- sufficiency associated with congr:~ital aortic stenosis, Circulation 34:87. 1966. Burch, G. E., DePasquale, X. I’., .:ncl Phil:++,

j. I-I.: Clinical manifestatioiz rrE papillar> muscle dysfunction, Arch, int. Med. 112:112, 1963,

452 Arosemena, Moller , and Edwards Am. Heart J. October, 1967

4. Moller, J. H., Lucas, R. V., Jr., Adams, P., Jr., Anderson, R. C., Jorgens, J., and Edwards, J. E.: Endocardial fibroelastosis. A clinical and anatomic study of 47 patients with empha- sis on its relationship to mitral insufficiency, Circulation 30:759, 1964.

5. Estes, E. H., Jr., Entman, M. L., Dixon, H. B., and Hackel, D. B.: The vascular supply of the left ventricular wall. Anatomic observa- tions, plus a hypothesis regarding acute events

in coronary artery disease, AM. HEART J. 7158, 1966.

6. Estes, E. H., Jr., Dalton, F. M., Entman, M. L., Dixon, H. B., II, and Hackel, D. B.: The anatomy and blood supply of the papillary muscles of the left ventricle, AM. HEART J. 71:356, 1966.

7. Kirk, E. S., and Honig, C. R.: Nonuniform distribution of blood flow and gradients of oxygen tension within the heart, Am. J. Phys- iol. 207:661, 1964.