Maria de Lourdes Higuchi
E n d o m y o c a r d i a l b i o p s y i n C h a g a s ' h e a r t d i s e a s e :
pathogenetic contributions
Heart Institute, Hospital das Clinicas, Faculdade de Medicina da
Universidade de Silo Paulo - Silo Paulo, Brazil
E n d o m y o c a rd ia l b io p s y p ro c e d u re h a s b e e n p e rfo rm e d in m a n y c e n te rs a ro u n d th e w o rld , a llo w in g a b e tte r tre a tm e n t a n d fo llo w -u p o f th e p a tie n ts w ith m y o c a rd ia l d is e a s e . In C h a g a s ' d is e a s e , it h a s b e e n p e rfo rm e d in S a o P a u lo H e a rt In s titu te s in c e 1 9 7 8 a n d
h a s b ro u g h t im p o rta n t c o n trib u tio n s to th e u n d e rs ta n d in g o f th e d is e a s e a n d c o n s e q u e n tly o f th e p a tie n t's c lin ic a l s ta g e . In th e p re s e n t w o rk w e s u m m a riz e th e p rin c ip a l fin d in g s re g a rd in g th e p a th o g e n e s is o f C h a g a s ' d is e a s e o b ta in e d m a in ly fro m th e s tu d ie s u s in g e n d o 'm y o c a rd ia l b io p s y s p e c im e n s . N o w a d a y s w e d o n o t h a v e d o u b ts th a t th e in fla m m a to ry in filtra te a g g re s s in g m y o c a rd ia l fib e rs h a s fu n d a m e n ta l ro le in th e p ro g re s s io n o f th e m y o c a rd ia l d a m a g e in C h a g a s ' d is e a s e w h a t c u lm in a te s in c h ro n ic
h e a rt fa ilu re . T h e p a ra s ite s e e m s to h a v e a c tiv e p a rtic ip a tio n in th e m a in te n a n c e o f s u c h m y o c a rd ia l in fla m m a tio n .
U N IT E R M S : E n d o m y o c a rd ia l b io p s y . C h a g a s ' d is e a s e . P a th o g e n e s is . Trypanosoma cruzi.Im m u n o p a th o lo g y .
IN T R O D U C T IO N
T
h ee n d o m y o c a r d i a ll o w l e v e l s o fb i o p s ym o r b i d i t yt e c h n i q u ea n dh a v em o r t a l i t ym a d e v e r yo f c o m m o n i t s u s e i n s e v e r a l c o n d i t i o n s . T h i st e c h n i q u e w a s d e s c r i b e d b y K o n n o e S a k a k i b a r a i n 1 9 6 3
( 1 0 ) a n d t h e m a i n i n d i c a t i o n h a s b e e n t h e d e t e c t i o n e a r l i e s t
a s p o s s i b l e a c u t e r e j e c t i o n e p i s o d e s i n t h e f o l l o w - u p o f
h e a r t t r a n s p l a n t e d p a t i e n t s . F r e q u e n t l y , m o r e t h a n 2 0
Addres.' ror correspondence:
Maria de Lourdes Higuchi
Instituto do Cora9ao - Hospital das Clfnicas da Faculdade
de Medicina da Universidade de Sao Paulo
Ali. Dr. Eneas de Carvalho Aguiar, 44 Sao Paulo - SP - Brasil - CEP 05403-000
c o n s e c u t i v e s e n d o m y o c a r d i a l b i o p s i e s a r e p e r f o r m e d i n a
s a m e p a t i e n t ( 1 7 ) . I t h a s a l s o b e i n g u s e d f o r t h e d i a g n o s i s
a n d c o n t r o l o f t h e t r e a t m e n t o f m y o c a r d i t i s .
E m p l o y m e n t o f t h e e n d o m y o c a r d i a l b i o p s y h a s
p r o v i d e d m a n y i m p o r t a n t c o n t r i b u t i o n s i n t h e
u n d e r s t a n d i n g o f t h e p a t h o g e n e s i s o f c h r o n i c C h a g a s '
d i s e a s e a n d i t m a y b e , i n t h e f u t u r e , a n i m p o r t a n t a u x i l i a r y
p r o c e d u r e i n t h e m o n i t o r i z a t i o n o f t h e t r e a t m e n t o f c h r o n i c
c h a g a s i c p a t i e n t s .
T h e l a c k o f r e l i a b l e a n a t o m o p a t h o l o g i c a l d a t a ,
m a i n l y r e g a r J i n g t h e i n d e t e r m i n a t e s t a g e , h a s c r e a t e d
d i f f i c u l t i e s i n t h e u n d e r s t a n d i n g o f t h e h e a r t f a i l u r e i n
c h r o n i c C h a g a s ' d i s e a s e . L o p e s e t a l . , i n 1 9 7 5 p u b l i s h e d
o n e o f t h e f e w m o r p h o l o g i c a l w o r k s a b o u t t h e
i n d e t e r m i n a t e f o r m b e f o r e t h e i n t r o d u c t i o n o f t h e
e n d o m y o c a r d i a l b i o p s y t e c h n i q u e , a n d s h o w e d t h a t c h r o n i c
c h a g a s i c p a t i e n t s w h o h a d d i e d d u e t o s u d d e n d e a t h ,
T h e in tro d u c tio n o f e n d o m y o c a rd ia l b io p s y
te c h n iq u e p e rm itte d to d e m o n s tra te v a ria b le d e g re e s o f
a n a to m o p a th o lo g ic a l a lte ra tio n s in 6 0 % o f th e c h a g a s ic
p a tie n ts in th e in d e te rm in a te fo rm , th a t is p a tie n ts w ith o u t
c a rd ia c c lin ic a l s y m p to m s , ra d io lo g ic a l o r
e le tro c a rd io g ra p h ic a l a lte ra tio n s (1 2 ).
C a rra s c o -G u e rra e t a I., in 1 9 8 7 (2 ), a ls o o b s e rv e d
th a t 6 0 % o f th e p a tie n ts w ith n o e v id e n c e o f m y o c a rd ia l
d is fu n c tio n (in d e te rm in a te fo rm ) p re s e n te d d e g e n e ra tiv e
a lte ra tio n s d e te c te d b y o p tic a l m ic ro s c o p y , u ltra s tru c tu ra l
a n a ly s is o r h is to c h e m ic a l s tu d y . T h e re w a s m a jo r in c id e n c e
a n d m o re s e v e rity o f s u c h a b n o rm a litie s in th e g ro u p s o f
p a tie n ts w ith e le tro c a rd io g ra p h ic a b n o rm a litie s . T h e
a u th o rs p ro p o s e d a n e w c la s s ific a tio n fo r c h ro n ic C h a g a s '
d is e a s e , u s in g e n d o m y o c a rd ia l b io p s y , c in e v e n tric u lo g ra m ,
a n d g ra d e o f h e a rt fa ilu re : z e ro (n o rm a l c in e v e n tric u lo g ra m
a n d n o rm a l b io p s y ), IA (n o rm a l E C G a n d n o rm a l c in e ,
b u t a b n o rm a l b io p s y ), IB (n o rm a l E C G , a b n o rm a l c in e
a n d a b n o rm a l b io p s y ), II (a b n o rm a l E C G , a b n o rm a l c in e
a n d a b n o rm a l b io p s y , w ith o u t h e a rt fa ilu re ) a n d III
(a b n o rm a l E C G , a b n o rm a l c in e a n d a b n o rm a l b io p s y w ith
c o n g e s tiv e h e a rt fa ilu re ).
P a la c io s - P rti e t a l. (1 6 ), q u a n tifie d th e m y o c a rd ia l
u ltra e s tru c tu ra l a lte ra tio n s a n d o b s e rv e d a n in c re a s e o f
s u c h le s io n s fro m g ra d e I-A u n till g ra d e II. T h e re w a s a
m ild d e c re a s e o f th e le s io n s in th e g ra d e III.
P e re ira -B a rre to e t a I., in 1 9 8 6 (1 8 ), s tu d ie d
e n d o m y o c a rd ia l b io p s y s p e c im e n s fo rm c h ro n ic c h a g a s ic
p a tie n ts in d iffe re n t c lin ic a l s ta g e s (in d e te rm in a te , c a rd ia c
fo rm w ith o u t h e a rt fa ilu re a n d c a rd ia c fo rm w ith h e a rt
fa ilu re ) a n d d e m o n s tra te d th a t h y p e rtro p h y a n d fib ro s is
w e re m o re fre q u e n t a n d m o re s e v e re ,in th e g ro u p o f
p a tie n ts w ith h e a rt fa ilu re . T h e in fla m m a to ry in filtra te
w a s p re s e n t in n e a rly 6 5 % o f th e p a tie n ts w ith
e le c tro c a rd io g ra p h ic a lte ra tio n s (w ith o r w ith o u t h e a rt
fa ilu re ) a n d in 3 7 % o f th e p a tie n ts in th e in d e te rm in a te
fo rm . H ig u c h i e t a I. (6 ), s tu d ie d e n d o m y o c a rd ia l b io p s y
s p e c im e n s fro m th e s a m e g ro u p s o f p a tie n ts lo o k in g fo r
a c tiv e m y o c a rd itis . In th is w o rk th e a u th o rs u s e d a s
c rite riu m o f a c tiv e m y o c a rd itis th e p re s e n c e o f
ly m p h o c y te s s u rro u n d in g m y o c a rd ia l fib e rs w h ic h w e re
in te rp re te d a s fo c i o f m y o c a rd ia l a g g re s s io n . T h e y
c o n c lu d e d th a t m y o c a rd itis is m o re fre q u e n t a n d m o re
s e v e re in th e g ro u p w ith c h ro n ic h e a rt fa ilu re (9 2 % ),
s e c o n d ly in th e g ro u p w ith o u t h e a rt fa ilu re (6 2 % ) a n d
ra re ly in th e in d e te rm in a te fo rm (1 5 % ).
A ll o f th e s e fin d in g s re in fo rc e d th e id e a th a t th e
in fla m m a tio n , m a in ly a tta c k in g th e m y o c a rd ia l fib e rs , h a s
a fu n d a m e n ta l ro le in th e e v o lu tio n o f th e c h ro n ic c h a g a s ic
c a rd io p a th y to h e a rt fa ilu re . T h e c lin ic a l e v o lu tio n o f th e
d is e a s e w o u ld re p re s e n t a c o n tin u o u s p ro g re s s io n o f
m y o c a rd ia l fib e rs d e s tru c tio n , s u b s titu tio n b y fib ro s is ,
c o m p e n s a to ry h ip e rtro p h y , c a rd ia c d ila ta tio n a n d h e a rt
fa ilu re .
T h e a c tiv e p a rtic ip a tio n o f th e in fla m m a to ry p ro c e s s
in th e p a th o g e n e s is o f c h ro n ic c a rd ia c C h a g a s ' d is e a s e
w a s c o n te s te d in th e p a s t (9 ). H o w e v e r, n o w a d a y s , m o s t
o f th e in v e s tig a to rs b e lie v e th a t im m u n o lo g ic a l re a c tio n s
s h o u ld b e in v o lv e d in th is p ro c e s s . T h e d is c re p a n c y
b e tw e e n p re s e n c e o f p a ra s ite s a n d in te n s ity o f
in fla m m a to ry in filtra te a n d th e d iffic u lty to fin d
T. cruzi
p a ra s ite s o rig in a te d m a n y a u to im m u n e o r h ip e rs e n s itiv ity
th e o rie s .
T h e fin d in g o f c irc u la tin g a u to a n tib o d ie s in c h ro n ic
c h a g a s ic p a tie n ts s u g g e s te d p a rtic ip a tio n o f h u m o ra l
a u to im m u n e p h e n o m e n o n (3 ). C o rro b o ra tin g th is id e a
M o lin a e t a I. (1 4 ), in 1 9 8 4 , d e te c te d Ig G , Ig A , Ig M a n d
C 3 in th e in te rs titiu m , c a p ila r, e n d o c a rd iu m a n d s u rfa c e
o f c a rd ia c fib e rs u s in g e n d o m y o c a rd ia l b io p s y in c h ro n ic
c h a g a s ic p a tie n ts , a n d d ire c t im m u n o flu o re s c e n t a n d
im m u n o h is to c h e m ic a l s tu d ie s . H o w e v e r, H ig u c h i e t a I. (8 )
d id n o t a n y fin d im m u n o g lo b u lin s o r c o m p le m e n t in th e
m y o c a rd iu m o f e n d o m y o c a rd ia l b io p s y s p e c im e n s fro m
c h ro n ic c h a g a s ic p a tie n ts p re s e n tin g h e a rt fa ilu re , a ls o
u s in g im m u n o flu o re s c e n c e te c h n iq u e c o n tra d ic tin g th e
id e a o f d ire c t p a rtic ip a tio n o f a u to a n tib o d ie s in th e
p a th o g e n e s is o f c h ro n ic c h a g a s ic m y o c a rd itis .
T h e in v o lv e m e n t o f c e llu la r a u to im u n ity w a s
in v e s tig a te d b y H ig u c h i e t a I. (7 ), th ro u g h th e d e te c tio n o f
w h ic h s u b s e ts o f T c e lls w e re p a rtic ip a tin g in c h ro n ic
c h a g a s ic m y o c a rd itis a n d c o m p a rin g w ith th e m y o c a rd ia l
re je c tio n p ro c e s s in n o n -c h a g a s ic h e a rt tra n s p la n te d
p a tie n ts . T h e a u th o rs c o n s id e re d th a t th e re je c tio n c o u ld
b e s e e n a s a n a u to im m u n e p ro c e s ,s , s in c e it is a re a c tio n o f
th e ly m p h o c y te s a g a in s t m y o c a rd ia l fib e rs w h ic h a re
c o n s id e re d a s n o n -s e lf. T h e m y o c a rd ia l re je c tio n p ro c e s s
w a s c h a ra c te riz e d b y s im ila r n u m b e rs o f C D 8 + a n d C D 4 +
T c e lls . In c o n tra s t, th e c h ro n ic c h a g a s ic m y o c a rd itis w a s
c h a ra c te riz e d a s a T c e ll m y o c a rd itis , m a in ly b y C D 8 +
a n d s c a rc e a n d w e a k ly s ta in e d C D 4 + c e lls . T h e a u th o rs
s u g g e s te d p a rtic ip a tio n o f th e p a ra s ite in d u c in g w e a k
e x p re s s io n o f C D 4 T c e lls e x p e rim e n ta l a c u te in fe c tio n
s in c e it is k n o w n e x p e rim e n ta lly th a t
T. cruzi
is a b le tod e c re a s e th e e x p re s s io n o f s u rfa c e C D m o le c u le s , c a u s in g
a im m u n o d e p re s s io n in th e h o s t (2 0 ).
In s p ite o f s o m e e x p e rim e n ta l w o rk s h a v e s u g g e s te d
th e p o s s ib ility o f d e v e lo p m e n t o f c h ro n ic c a rd io p a th y o n ly
in je c tin g fra g m e n ts o f th e p a ra s ite a n d c o n s e q u e n tly th e
d is e a s e to b e a s s o c ia te d to a n a u to -im m u n e p ro c e s s (2 1 ),
th e re a l s ig n ific a n c e o f th e p a ra s ite in th e p a th o g e n e s is o f
c h ro n ic le s io n s o f C h a g a s ' d is e a s e is d e m a n d in g m o re
Figure 1. Histopathological picture of human chronic chagasic myocarditis exhibiting intracellular
T.
cruzi
antigens, detected by specific immunohistochemical reaction. (IPX 160x)(5 ), u s in g p o lic lo n a l a n ti-:r.
cruzi
a n tig e n . W e d e m o n s tra te da d ire c t a s s o c ia tio n b e tw e e e n p re s e n c e o f:r.
cruzi
a n tig e n sa n d p re s e n c e o f m o d e ra te o r s e v e re m y o c a rd ia l
in fla m m a tio n . T h e :r.
cruzi
w e re s e e n a s ro u n d e d s tru c tu re ss im ila r to d e g e n e ra te d a m a s tig o te s in th e in te rs titia l m a trix (F ig .2 ), a m o rp h o u s m a te ria l in to th e c ito p la s m o f th e
m a c ro p h a g e s (F ig . 1 ), o r a s a m a s tig o te s in to m y o c a rd ia l fib e rs o r e n d o th e lia l c e lls . H o w e v e r, th e n u m b e r o f
p a ra s ite s w a s g e n e ra lly s c a rc e th a t it d id n o t ju s tify th e
in te n s ity o f m y o c a rd ia l in fla m m a tio n , s u g g e s tin g th a t, in
p a ra lle l to th e a c tio n o f th e p a ra s ite s , o th e r p ro c e s s e s a s a u to im m u n ity o r h ip e rs e n s itiv ity s h o u ld b e p a rtic ip a tin g .
T h e p re s e n c e o f:r.
cruzi
s tru c tu re s o u ts id e o f th e c e lls , ino u r o p p in io n , is a v e ry im p o rta n t s tim u lu s fo r d e v e lo p m e n t o f a c tiv e m y o c a rd itis e p is o d e s , in c lu d in g a g g re s s io n o f
n o n -in fe c te d m y o c a rd ia l fib e rs (a u to -a g g re s s io n ). T h is
fin d in g c o rro b o ra te p re v io u s th e s is o f h ip e rte n s itiv ity o f
m a n y a u th o rs d e c a d e s b e fo re . M a g a rin o T o rre s , in 1 9 2 9
(1 3 ), p ro p o s e d th e o c c u rre n c e o f h ip e rs e n s itiv ity p h e n o m e n o n s in d u c e d b y a n tig e n ic p ro d u c ts re le a s e d b y
d e g e n e ra te d p a ra s ite s , to e x p la in th e c a rd ia c in fla m m a to ry le s io n s . M u n iz e A z e v e d o in 1 9 4 7 (1 5 ), p ro d u c e d
in fla m m a to ry le s io n s in h e a rts o f m o n k e y s u s in g s u c c e s s iv e in je c tio n s o f :r.
cruzi
c u ltu re s . B rito in 1 9 6 2Figure 2. Histopathological aspect from another human case of chronic chagasic myocarditis showing three degenerated
T.
cruzi
amastigotes (through immunoperoxidasis technique) near to the sarcolemma of a myocardial fiber surrounded by moderate mononuclear inflammatory infiltrate. (IPX 400x)(1 ) p ro d u c e d c h ro n ic m y o c a rd itis in g u in e a -p ig s in je c tin g
h o m o g e n a te s o f h e a rt a s s o c ia te d to :r.
cruzi
a n tig e n a n d F re u n d a d ju v a n t, c o n c lu d in g th a t h ip e rs e n s itiv ity h a d afu n d a m e n ta l ro le in th e p a th o g e n e s is o f th is m y o c a rd itis .
F ra n c o , in 1 9 7 2 (4 ), a n a ly s e d a c u te a n d c h ro n ic in fe c tio n
in g u in e a -p ig s a n d v e rifie d p re s e n c e o f :r.
cruzi
a n tig e n sin m a c ro p h a g e s d u rin g a l~ o th e c h ro n ic s ta g e o f th e d is e a s e , s u g g e s tin g th a t th e p e rs is te n c e o f th e s e a n tig e n s in
in te rs titia l m a c ro p h a g e s w o u ld in d u c e th e h ip e rs e n s itiv ity
re a c tio n s . A n o th e r d a ta fa v o u rin g th e c o n c e p t o f c h ro n ic
in flu e n c e o f th e p a ra s ite c o m e s fro m th e o b s e rv a tio n o f c h ro n ic c h a g a s ic p a tie n ts s u b m itte d to h e a rt
tra n s p la n ta tio n . T h e s e p a tie n ts fre q u e n tly p re s e n t e p is o d e s o f re a c ti v a tio n o f th e C h a g a s ' d i s e a s e a fte r
im m u n o s u p p re s s io n (1 9 ) in d ic a tin g th a t th e p a ra s ite
re m a in s in c o n s ta n t im m u n o lo g ic a l c o n tro l in c h ro n ic
p h a s e o f th e d is e a s e . T h a n , if m y o c a rd itis o c c u rs in th e e n d o m y o c a rd ia l b io p s ie s o f th e s e p a tie n ts , it is n e c e s s a ry
to s e a rc h
T.
cruzi
a n tig e n s a t th e m y o c a rd ia l s e c tio n s ino rd e r to d iffe re n tia te m y o c a rd ia l re je c tio n p ro c e s s fro m c h ro n ic c h a g a s ic m y o c a rd itis , b e c a u s e b o th p ro c e s s e s h a v e
th e s a m e h is to lo g ic a l fe a tu re . In c a s e o f C h a g a s ' d is e a s e re a c tiv a tio n , tre a tm e n t w ith s p e c ific a n tip a ra s itic d ru g
infiltrate.
After all these findings
we are convinced
that
parasite has significant influence in determining
the active
chronic myocarditis
and that the endomyocardial
biopsy
may have important role in the follow up ofthese patients.
In our oppinion,
chronic chagasic
patient with moderate
..'
....
. >::. ~/:.": :•..,.•.:....~..•.•'.
"):
.:..::.::/:.:...:
or severe
inflammation
at the endomyocardial
biopsy
probably presents any grade of
T. cruzi
reactivation,
and
new therapeutic
purposes should be developed
in order to
REFERENCES
I. BRITO, T. - Miocardite "alergica" do cobaio e sua possivel rela~ao com a cardite chagasica experimental. Sao Paulo, 1962 [Tese Doutoramento - Universidade de Sao Paulo]. 2. CARRASCO GUERRA, H.A.; PALAcIOS-PRU, E.;
SCORZA, C.D.; MOLINA, C.; INGLESSIS, G.
&
MENDOZA, R.Y. - Clinical, histochemical and ultrastructural correlation in septal endomyocardial biopsies from chronic chagasic patients: Detection of early myocardial damage. Am Heart J 113:716-24, 1987.
3. COSSIO, P.M.; DIEZ, D.; SZARFMAN, A. & ARANA, RM. - Chagasic cardiopathy. Demonstration of a serum gamma globulin factor which reacts with endocardium and vascular structures. Circulation 49: 13-21, 1974.
4. FRANCO, M.F. - Experimental carditis induced by
TI)Jpanosoma
end
(Y strain) in guinea pigs: correlation between histopathology and the presenceofT
end
antigensidentified by indirect immunofluorescence. Rev Soc Bras Med Trop 23: 187-89, 1990.
5. HIGUCHI, M.L.; BRITO, T.; REIS, M.M. et al. - Correlation between
Trypanosoma
cruzi
parasitism and myocardial inflammatory infiltrate in human chronic chagasic myocarditis. Light microscopy and immunohistochemical findings. Cardiovasc Pathol 2: 101-6, 1993.6. HIGUCHI, M.L.; DE MORAIS, C.F.; PEREIRA-BARRETO, A.C. et al. - The role of active myocarditis in the development of heart failure in chronic Chagas' disease: a study based on endomyocardial biopsies. Clin Cardiol 10:665-70, 1987.
7. HI9UCHI, M.L.; GUTIERREZ, P.S.; AIELLO, VD. et al. -Immunohistochemical characterization of infiltrating cells in human chronic chagasic myocarditis: comparison with myocardial rejection process. Virchows Archiv A Pathol Anat 423:157-60, 1993.
8. HIGUCHI, M.L.; LOPES, E.A.; SALDANHA, L.B. et al. -Immunopathologic studies in myocardial biopsies of patients with Chagas' disease and idiopathic cardiomyopathy. Rev Inst Med Trop Sao Paulo 28: 87-90, 1986.
9. KOBERLE, F. - Cardiopatia chagasica. Hospital (Rio de Janeiro) 53: 311-46, 1958.
10. KONNO, S.
&
SAKAKIBARA, S. - Endomyocardial biopsy. Dis Chest 44:345-50, 1963.II. LOPES, E.R.; CHAPADEIRO, E.; ALMEIDA, H.O.
&
ROCHA, A. - Contribui~ao ao estudo da anatomia patol6gica dos cora~5es de chagasicos falecidos subitamente. Rev Soc Bras Med Trop 6: 269-82, 1975.
12. MADY, C.; PEREIRA, A.; STOLF, N. et al. - Right ventricular endomyocardial biopsy in undetermined form of Chagas' disease. Angiology 35:755-8, 1984.
13 MAGARINO- TORRES, C.B. - Patogenia de la miocardite cronica de la "enfermedad de Chagas". Quinta Reunion de la Sociedad Argentina de Patologia Regional do Norte 2: 902-16, 1929.
14. MOLINA, H.A.; MILEI, J.
&
STORINO, R. - Chronic Chagas' myocardiopathy. Demonstration of in vivo bound immunoglobulins in heart structures by the immunoperoxidase technique. Cardiology 71:297-306, 1984.15. MUNIZ, 1.
&
AZEVEDO, A.P. - Novo conceito da patogenia da Doen~a de Chagas. Hospital (Rio de Janeiro) 32: 165-83, 1977.16. PALAcIOS-PRU, E.; CARRASCO, H.; SCORZA, C.
&
ESPINOZA, R. - Ultrastructural characteristics of different stages of human chagasic myocarditis. Am J Trop Med Hyg 4: 29-40, 1989.
17. PEREIRA-BARRETO, A.C.; COSTA, R; HIGUCHI, M.L. et al. - Bi6psia endomiocardica do ventrfculo direito - 9 ar10S (1978-1987). Arq Bras Cardiol 49: 147-9, 1987.
18. PEREIRA-BARRETO, A.C.; MADY, C.; ARTEAGA-FERNANDEZ, E. et al. - Right ventricular endomyocardial biopsy in chronic Chagas' disease. Am Heart J 111:307-12, 1986.
19. STOLF, N.A.; HIGUCHI, M.L.; BOCCHI, E. et al. - Heart transplantation in patients with Chagas' disease cardiomyopathy. J Heart Transpl 6:307-12, 1987. 20. SZTEIN, M.; W ASHINGTON, RC. & KIERSZENBAUM,
F. -
