Marcos
A .Rossi
P a th o g e n e sis o f c h ro n ic C h a g a s' m y o c a rd itis
Department of Pathology, Faculdade de Medicina de Ribeirao Preto
Universidade de sao Paulo.
sao Paulo, Brazil
The pathogenesis of chronic Chagas' myocarditis is still not completely understood. Several theories have been advanced:
1)
direct tissue destruction by Trypanosoma cruzi;
2 )neurogenic theory;
3 )anti-heart immune reactions; and
4 )microvascular
disease.
W epresent herein
adynamic alternative hypothesis.
W ebelieve that the development of myocarditis is related to
progressive and additive focal cellular necrosis, and associated reactive and reparative myocardial fibrosis and surrounding
myocyte hypertrophy. These processes may be initiated and perpetuated by anti immune factors and alterations in the myocardial
microcirculation. The destruction of the ganglion cells of the heart may be involved in the patho-clinical evolution of chronic
Chagas' cardiopathy. This could imply future therapeutic strategies in the management of chronic Chagas' patients to enhance
medical treatment and, hopefully, improve prognosis.
U N IT E R M S : M y o c a rd itis . C h a g a s 's d is e a s e .
IN T R O D U C T IO N
C
h a g a s 'Trypanosoma
d is e a s e ,crud,
c a u s e dis o n eb yo f th eth e tr a n s m is s io ng r e a te s t p u b lico f h e a lth p r o b le m s f a c e d b y m a n y L a tin A m e r ic a n c o u n tr ie s , a n d in r e g io n s r a n g in g f r o m th e s o u th e r n U n ite d S ta te s to A r g e n tin a ( 5 3 ) . T h e d is e a s e is c h a r a c te r iz e d b y th r e e p h a s e s : a c u te , la te n t a n d c h r o n ic ( l,4 3 ) . T h e m o s t im p o r ta n t v is c e r a l in v o lv e m e n t is th a t o f th e h e a r t. D u r in gAddress for Correspondence:
Marcos
A .Rossi
Departamento
de Patologia - Faculdade de Medicina de
Ribeirao Preto - Universidade
de Sao Paulo
Ribeirao Preto -
S P -Brasil-
CEP 014049-900
th e a c u te p h a s e th e d e g r e e o f m y o c a r d ia l in v o lv e m e n t v a r ie s f r o m s lig h t a s y m p to m a tic o r o lig o s y m p to m a tic to s e r io u s , e v e n f a ta l, f o r m s . T h e s e s e r io u s f o r m s a r e n o t f r e q u e n t, m a k in g u p ju s t 3 .5 % o f th e c a s e s . D u r in g th e in itia l s ta g e s o f th e c h r o n ic p h a s e th e p a tie n t m a y b e a s y m p to m a tic o r s h o w s o m e s y m p to m s r e la te d w ith h e a r tb e a t d is tu r b a n c e ; d u r in g in te r m e d ia te s ta g e s , c lin ic a l m a n if e s ta tio n p e r s is ts o r in te n s if ie s , h e a r t e n la r g e m e n t m a y b e d e te c te d , v a r y in g f r o m s lig h t to m o d e r a te ; in th e f in a l s ta g e h e a r t e n la r g e m e n t is m o r e p r o n o u n c e d p lu s s e r io u s c o n g e s tiv e c a r d ia c f a ilu r e , th r o m b o e m b o lic p h e n o m e n o n a n d s e r io u s a r r h y th m ia . S u d d e n d e a th is a c o n s ta n t r is k a t a n y s ta g e o f th e d is e a s e . T h e la te n t p h a s e is th e in te r m e d ia te p e r io d s e p a r a tin g th e a c u te a n d c h r o n ic o n e s , a n d is u s u a lly lo n g la s tin g ( f r o m 1 0 to 2 0 y e a r s ) . L ittle is k n o w n r e g a r d in g th e c lin ic a l p a th o lo g ic a l m a n if e s ta tio n s .
T he
pathology
reflects
the im portance
of cardiac
involvem ent
in C hagas'
disease
(20). D uring
the acute
phase, the heart is globous and flaccid; regions of m yocytic
necrosis
and
m yocellular
degeneration
can be observed
m icroscopically
w ith
intense
infiltrated
lym phom ononuclear
inflam m ation
associated
w ith
exudative
phenom enon
and m yofiber
parasitism .
D uring
the chronic phase, cardiopathy
is polym orph,
w ith varying
degrees of hypertrophy
and dilation. A pical aneurysm
m ay
or m ay
not be present.
A focused
or diffuse
infiltrated
lym phom ononuclear
inflam m ation
m ay be m icroscopically
observed,
plus
regions
of
m yocytic
necrosis
and
degeneration
of m yocardial
cells,
interstitial
fibrosis
of
varying degrees
and rare fibers w ith intracellular
parasites.
T he
C hronic
C hagas'
M yocarditis
P athogenesis
is,
how ever,
not com pletely
understood.
S everal
different
types of treatm ent
have been proposed.
DIRECT TISSUE lESION
BY TRYPANOSOMA CRUZI
L esions
m ay be caused
by continued
invasion
of the
m yocardium ,
by localized
liberation
of toxins,
or both.
Insignificant
parasitem ia
levels and the occasional
finding
of parasitic
pseudocysts
are argum ents
against the theory
that
m yocardial
lesions
are
directly
correlated
to the
presence
of the parasites.
H ow ever
a possible
relationship
betw een
the presence
of the T . cruzi im m unogens
and the
intensity
of inflam m atory
infiltrate
has been observed
in
autopsied
chronic
C hagas'
patients,
suggesting
therefore
that
the
parasite
has
a role
in perpetuating
chronic
m yocarditis
(15).
NEUROGENIC THEORY
C hronic
m yocardiopathy
caused by C hagas'
disease
can
be
considered
as cardioneuropathy
due
to
the
destruction
of the heart's
parasym pathetic
ganglionic
cells
(20,29).
H istological
studies
show
an
accentuated
reduction
in the
num ber
of parasym pathetic
cardiac
neurons in proportion
to the alterations
in heart pathologies
(20,29).
T hese
observations
have
been
contested
by
researchers
w ho
have
noticed
an absence
of neuronal
lesion
at the
onset
of the
disease,
and no relationship
betw een
the neuronal
count
and the disease's
progress.
M yocardial
lesions
and
discrete
ventricular
dilation
preceded
parasym pathetic
functional
heart
abnorm alities
in C hagas'
patients.
H ow ever,
results
of recent functional
studies
have confirm ed
the occurrence
of abnorm alities
of the
regulating
neural
heart
m echanism s
in chronic
C hagas'
patients
w ithout
cardiac
insufficiency.
ANTIMYOCARDIAl
IMMUNOLOGICAL
REACTIONS
T he action of self im m une
m echanism s
has been held
to be the
m ain
cause
of chronic
C hagas'
m yocarditis
(1,18,30,43).
S etting
up an experim ental
m odel
w hich
could
provide
evidence
in favor of this theory
to allow
reliable
im m unological
handling
w ould
be extrem ely
im portant.
W e have
show n
in a recent
study
that
lab
m ice
w hen
chronically
infected
by
T.
cruzi
w ere capable
of rejecting
syngenical
hearts
of new -born
ear-transplanted
anim als
(32).
T ransplanted
syngenical
heart
rejection
happened
quicker
than
w hen
com pared
to an allogenic
situation.
T hese
observations
w ere in com plete
contrast
to norm al
or
T.
cruzi
hyperim m unized
syngenic
receivers
w ith
transplanted
organs,
w hich
lasted
for
m onths.
T he
histological
study of transplanted
cardiac tissue in C hagas'
m ice
revealed
intense
and
persistent
m ononuclear
inflam m atory
infiltrate,
sim ilar
to that
obtained
under
allogenic
conditions,
thus
indicating
the
im plication
of
cellular
m echanism s.
A series
of tests
w as carried
out to determ ine
the
phenotype
of those
cells
involved
in syngenical
heart
rejection
phenom ena
(F igure
1). T C D 4 cell depletion
in
vivo,
but not C D 8 cells caused
cell rejection
to be halted,
i.e. cardiac
transplants
survived
in chronically
infected
m ice treated w ith anti C D 4 m onoclonal
antibody
(32). A nti
C 24 m onoclonal
antibodies
have been used successfully
in sim ilar experim ents
to show the tolerance
induction
in
L angerhaus
islets allotransplantation
in m ice, or allogenic
heart transplants
in rats (44,45).
In vivo
studies
w ith
T
C D 4 lym phocyte
from chronically
infected m ice by
T.
cruzi
have
show n
that,
injected
in situ,
it brings
about
the
destruction
of syngenic
transplants
of norm al
m ice hearts
(32). O n the other hand, T C D 8 cells or non T cells w ere
ineffective.
T hese
results,
w hen
analyzed
collectively,
dem onstrated
that self reactivity
is restricted
to T C D 4
cell
division,
in contrast
to skin
allogenic
transplant
rejection
attributed
to the T C D 4
and C D 8
lym phocytes
(6,19).
T he
observation
that
the
m ajority
of T cells
infiltrating
the m yocardium
during
the acute and chronic
phases
of
the
T.
cruzi
experim ental
infection,
Figure 1.
S c h e m a tic r e p r o d u c tio n o f tr a n s p la n te d h e a r t r e je c tio n d e p e n d e n t o n T C D 4 ly m p h o c y te s . ( A ) C h r o n ic a lly in fe c te d m o u s e tr a n s p la n te d w ith s y n g e n ic h e a r ts . R e je c tio n is a v o id e d b y tr e a tm e n t w ith A n ti- C D 4 m o n o c lo n a l a n tib o d y , b u t n o t b y a nti-C O B . ( 8 ) N o n in fe c te d c o n tr o l m o u s e tr a n s p la n te d u s in g s y n g e n ic h e a r ts . T C D 4 s p le n ic c e lls , b u t n o t C O B , fr o m c h r o n ic s y n g e n ic
C h a g a s ' d o n o r s a r e c a p a b le o f a c u te ly r e je c tin g im p la n te d h e a r ts
c o r r e s p o n d i n g t o T C D 4 l y m p h o c y t e s f a v o r s t h i s t h e o r y .
T h i s a l s o c o n c u r s w i t h o t h e r s p e c i f i c s e l f i m m u n e d i s e a s e
e x p e r i m e n t a l m o d e l s , w h e r e t h e T C D 4 c e l l s c a r r y o u t a n
i m p o r t a n t r o l e i n i n d u c i n g t i s s u e l e s i o n s ( 3 9 , 4 1 ) . I t h a s
b e e n s h o w n t h a t T C D 4 l y m p h o c y t e s m o d u l a t e a n t i b o d y
p r o d u c t i o n , m a c r o p h a g e a c t i v a t i o n , a n d i n d u c e l e s i o n s i n
t h e e x p e r i m e n t a l t r y p a n o s o m i a s i s c r u z i ( 1 6 , 2 4 , 3 5 , 3 8 ) .
I t i s k n o w n t h a t t h e e x p r e s s i o n C D 4 c o r r e l a t e s w i t h
t h e c e l l 's c a p a c i t y t o r e c o g n i z e a n t i g e n s c o n n e c t e d w i t h
c l a s s I I m o l e c u l e s ( 1 2 , 4 7 ) . A s n o f o r m a l d e m o n s t r a t i o n
e x i s t s t h a t m y o c y t e s c a n e x p r e s s c l a s s I I m o l e c u l e s i n t h e
m e m b r a n e , i t s e e m s u n l i k e l y t h a t T C D 4 c e l l s a r e
r e s p o n s i b l e f o r t h e f i n a l c y t o t o x i c e f f e c t o r " a c t i v i t y . W e h a v e
r e c e n t l y r e l a t e d t h a t t h e r e d r u t h e n i u m s t r o n g l y m a r k s t h e
m y o c y t e s ' c y t o p l a s m i c c o m p o n e n t s a t t h e p o i n t o f c o n t a c t ,
o r i n c l o s e a p p r o x i m a t i o n o f t h e m a c r o p h a g e s , i n d i c a t i n g
a l t e r e d a r e a s o f t h e p l a s m a t i c m e m b r a n e w i t h a n i n c r e a s e
i n p e r m e a b i l i t y . T h e s e o b s e r v a t i o n s s u g g e s t t h a t t h e
m o n o n u c l e a r c e l l w i t h t h e a p p e a r a n c e o f a c t i v a t e d
m a c r o p h a g e w o u l d b e t h e e f f e c t o r c e l l w h i c h i n j u r e s t h e
m y o c y t e s . I n t h i s c a s e T C D 4 l y m p h o c y t e s w o u l d
r e c o g n i z e t h e m y o c a r d i a l a n t i g e n s t o g e t h e r w i t h t h e c l a s s
I I a n t i g e n s e x p r e s s e d i n r e s i d e n t m a c r o p h a g e s o r d e n d r i t i c
c e l l s , a c t i v a t i n g t h e T C D 4 c e l l s , w i t h a s u b s e q u e n t
p r o d u c t i o n o f i n t e r l e u c i n ( 4 6 ) . T h u s a n i n f l a m m a t o r y
p r o c e s s w o u l d b e g i n , i n d u c i n g t h e d e s t r u c t i o n o f t h e
m y o c a r d i a l t i s s u e .
A n i n t e r e s t i n g q u e s t i o n b r o u g h t u p f r o m t h i s d a t a
r e f e r s t o s e l f r e a c t i n g T C D 4 l y m p h o c y t e a c t i v a t i o n . T h e
m o l e c u l a r m i m e t i s m b e t w e e n m y o c a r d i u m a n t i g e n s a n d
T.
cruzi
m a y b e u l t i m a t e l y r e s p o n s i b l e ( 5 0 ) .H o w e v e r ,
T.
crud
h y p e r i m m u n i z e d m i c e d o n o t r e j e c t s y n g e n i c a l h e a r t t r a n s p l a n t s . A p a r t f r o m t h i s t h e C D 4 c e l l so f t h e s e m i c e , i n j e c t e d
in situ,
d o n o t d e s t r o y t h e i m p l a n t s a n d d o n o t p r o l i f e r a t ein vitro
i n t h e p r e s e n c e o f h e a r t a n t i g e n s ( 3 2 ) . A c u t e i n f e c t i o n a n d l a r g e l e s i o n s o f t h e t a r g e to r g a n w o u l d b e n e c e s s a r y t o c a u s e t h e r u p t u r e o f t h e
t i s s u e s ' s p e c i f i c t o l e r a n c e . A s a n e x a m p l e , d u r i n g t h e a c u t e
p h a s e o f t h e d i s e a s e
T.
cruz
a n t i g e n s w o u l d c o p y t h em y o c a r d i a l c e l l s a n d i n c r e a s e t h e t i s s u e l e s i o n i n d u c e d b y
t h e i m m u n e r e s p o n s e t o t h e p a r a s i t e ( 3 1 ) . T h e p o l i c i n g
a c t i v a t i o n o f t h e T a n d B c e l l s w o u l d p l a y a n i m p o r t a n t
p a r t d u r i n g t h e
T.
crud
i n f e c t i o n 's a c u t e p h a s e h a v i n g a ni m p o r t a n t r o l e i n t h e d e v e l o p m e n t
a posteriori
o f t h ed i s e a s e 's s e l f i m m u n i t y . T o d a t e , w e s u p p o r t t h e t h e o r y
t h a t e x t e n s i v e t i s s u e l e s i o n s a n d s e l f i m m u n e d y s f u n c t i o n
d u r i n g t h e a c u t e p h a s e , m o r e t h a n c r o s s e d r e a c t i v i t y
b e t w e e n i t s o w n a n d
T.
cruzi
a n t i g e n s , w o u l d b e a b s o l u t e l y e s s e n t i a l f o r o r g a n - s p e c i f i c s e l f - i m m u n i t y i n t h e c h r o n i cp h a s e t o a p p e a r . C h r o n i c a l l y
T.
cruzi
i n f e c t e d i s o g e n i c m i c e s h o w T C D 4 l y m p h o c y t e s r e s p o n s i v e t o m y o s i n ( 3 3 ) . T h el i b e r a t e d m y o s i n d u e t o c e l l u l a r l e s i o n w o u l d b e p r o c e s s e d
a n d s h o w n b y r e s i d e n t m a c r o p h a g e s o r b y c e l l s d e n d r i t i c
t o t h e T C D 4 c e l l s w h i c h m o d u l a t e a n t i b o d y p r o d u c t i o n ,
a n d b y i n d u c i n g m a c r o p h a g e a c t i v a t i o n a n d s u b s e q u e n t
t i s s u e l e s i o n . A p a r t f r o m t h i s , e v i d e n c e s u g g e s t s t h a t t h e
T - c e l l s p l a y a p a r t i n t h e f i b r o s i s p a t h o g e n e s i s , a c t i n g
d i r e c t l y o n t h e f i b r o b l a s t s , b y d r a w i n g u p c y t o c i n s , o r
i n d i r e c t l y b y a m p l i f y i n g m a c r o p h a g e a c t i v i t y ( 2 1 ) .
T h e s e f i n d i n g s a l l o w u s t o c o n c l u d e t h a t s e l f
i m m u n i t y i s t h e p r i n c i p l e m e c h a n i s m i m p l i e d i n t h e
r e j e c t i o n o f t r a n s p l a n t e d s y n g e n i c c a r d i a c t i s s u e i n t h e e a r
o f c h r o n i c a l l y
T.
cruzi
i n f e c t e d m i c e . T h e s i m i l a r i t y o f t h e l e s i o n s t o t h o s e o b s e r v e d i n h u m a n s s u g g e s t s t h a t s e l fi m m u n i t y i s i n v o l v e d i n h u m a n C h a g a s ' m y o c a r d i t i s
p a t h o g e n e s i s . T h i s m a y i m p l y t h e r a p e u t i c s t r a t e g i e s f o r
r e - e s t a b l i s h i n g t h e c h r o n i c s p e c i f i c t o l e r a n c e b y t r e a t m e n t
w i t h a n t i - C D 4 m o n o n u c l e a r a n t i b o d i e s , m e d i a t i n g e n e r g y
o r t h e s u p p r e s s i o n o f r e s p o n s i v e T C D 4 c e l l s .
W i t h i n t h i s c o n t e x t , a n i m p o r t a n t a s p e c t t o b e t a k e n
i n t o c o n s i d e r a t i o n i s t h a t r e l a t e d t o t h o s e f a c t o r s w h i c h
c o n t r i b u t e t o t h e p r o g r e s s i o n f r o m t h e a c u t e p h a s e t o t h e
i n t e r m e d i a t e p h a s e o f C h a g a s ' d i s e a s e a n d t o t h o s e f a c t o r s
i n v o l v e d i n t h e p r o g r e s s i o n f r o m t h e i n t e r m e d i a t e p h a s e
t o t h e d i s e a s e 's c h r o n i c p h a s e . I t h a s b e e n p r o p o s e d t h a t T C O B c e ll tr a n s fe r
fr o m c h a g a s ic m ic e In je c te d in vivou s in g
a c M o A n ti- C D 4
T C D 4 c e ll tr a n s fe r fr o m c h a g a s ic m ic e In je c te d in v iv o u s in g a c M o A n ti- C O B
B A
d a m a g e to th e s u p p re s s in g im m u n o lo g ic a l n e tw o rk c o u ld
p la y a p a rt in m y o c a rd ia l le s io n p a th o g e n e s is , in b o th th e
a c u te a n d c h ro n ic p h a s e s (2 ,4 2 ).
M I C R O V A S C U L A R
D I S E A S E
It h a s b e e n re c e n tly b e e n c la im e d th a t m ic ro v a s c u la r
a b n o rm a litie s p la y a s ig n ific a n t p a rt 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 ' c a rd io p a th y (8 ,2 6 ,3 6 ,3 4 ,3 7 ,4 9 ). T h e
fo c a l n a tu re o f m y o c y to lic n e c ro s is a s s o c ia te d w ith
in te rs titia l fib ro s is a n d m o n o n u c le a r in fla m m a to ry in filtra te
in c h ro n ic C h a g a s ' m y o c a rd itis s u g g e s ts th a t th e
m ic ro c irc u la to ry s y s te m m a y b e a t c a u s e , i.e . th e d is e a s e 's
p rim a ry lo c a tio n m a y b e c a p a b le o f c a u s in g fo c a l n e c ro s is
in c e lls o f d is c re te g ro u p in g s . T h e in v o lv e m e n t o f s m a ll
v e s s e ls h a s b e e n p re v io u s ly re la te d b y o n ly a fe w a u th o rs ,
re fe rrin g to h u m a n C h a g a s ' d is e a s e a s w e ll a s th e
e x p e rim e n ta l fie ld . N e c ro tiz in g a rte ritis h a s b e e n o b s e rv e d
in h e a rt b io p s ie s in c a s e s o f h u m a n C h a g a s '
m e g a e s o p h a g u s (5 ), a n d in th e d ig e s tiv e tra c t o f
e x p e rim e n ta lly
T.
cruzi
in fe c te d m ic e (2 8 ). C o m p a ra tiv es tu d ie s o f h u m a n s b e tw e e n C h a g a s ' h e a rts a n d n o n
C h a g a s ' h e a rts s h o w irre g u la ritie s a n d c o n s tric tio n s o f
in tra m y o c a rd ia l a rte rio la r v e s s e ls a n d e x te n s iv e m y o c y litu s
w ith th e g ro u p o f C h a g a s ' d is e a s e s u ffe re rs (5 1 ,5 2 ). It w a s
th e n p ro p o s e d th a t th e d iffu s e m y o c y litu s o b s e rv e d in
c h ro n ic C h a g a s ' m y o c a rd io p a th y w o u ld re s u lt in m e ta b o lic
c h a n g e s to th e m y o c e lls d u e to th e lo w in te n s ity c irc u la to ry
c h a n g e s o f s h o rt d u ra tio n (5 2 ). H is to to p o g ra p h ic s tu d y ,
c o m p a rin g th e m ic ro c irc u la to ry s y s te m in C h a g a s ' h e a rts
a n d c o n tro ls in tra v a s c u la r p o s t-in je c tio n o f a n o p a q u e
m e d iu m , d e m o n s tra te d fo c a l C h a g a s ' d e c a p illa riz a tio n ,
c h a ra c te riz e d b y a n a c c e n tu a te d re d u c tio n in n u trie n t
filifo rm s , b e in g th e p ro b a b le c a u s e o f fo c a l m y o c y to ly tic
n e c ro s is (1 7 ).
P la te le t th ro m b o s is in s m a ll e p i a n d in tra m y o c a rd ia c
c o ro n a ry v e s s e ls p lu s h is to c h e m ic a l e v id e n c e o f th e
p re s e n c e o f m y o c a rd ia l h y p o x ia fo c u s w e re o b s e rv e d in
m ic e c h ro n ic a lly in fe c te d w ith th e
T.
cruzi
C o lo m b ia s tra in(3 6 ,3 7 ). T h e s e fin d in g s le a d u s to b e lie v e th a t th e
c o n s e q u e n c e s o f th e in fe c tio n c o n v e rg e o n th e c a rd ia c
m ic ro v a s c u la tu re , re s u ltin g in a re a s o f h y p o p e rfu s io n ,
Trypanosoma cruzi
A c t i v e m a c r o p h a g e s
i n d u c e t i s s u e l e s i o n s L i b e r a t e d c e l l c o n s t i t u e n t s
( e . g . m y o s i n ) a r e c a p t u r e d ,
p r o c e s s e d a n d a p p e a r a s
m a c r o p h a g e s o r d e n d r i t i c c e l l s
A c t s d i r e c t l y o n t h e f i b r o
-b l a s t s o r i n d i r e c t l y , b y
a c t i v a t i n g m a c r o p h a g e s C o n c e n t r a t i o n s o f
m y o c y t o l y t i c n e c r o s i s
T i s s u e o c c u r r e n c e s a s s o c i a t e d
w i t h i n f e c t i o n h a r m
m i c r o v a s c u l a r f u n c t i o n
F i g u r e 2 . A t h e o r e t i c a l s c h e m a t i c r e p r e s e n t a t i o n 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 ' m y o c a r d i t i s . M y o c a r d i t i s ' d e v e l o p m e n t i s r e l a t e d t o p r o g r e s s i v e a n d a c c u m u l a t e d l o c a l c e l l u l a r n e c r o s i s , a s s o c i a t e d w i t h r e p a r a t i v e a n d r e a c t i v e i n t e r s t i t i a l f i b r o s i s a n d c i r c u m j a c e n t m y o c y t a r i c h y p e r t r o p h y . T h e s e p r o c e s s e s b e g i n a n d a r e p e r p e t u a t e d b y s e l f i m m u n e f a c t o r s a n d b y c h a n g e s i n m y o c a r d i u m m i c r o c i r c u l a t i o n .
re g io n s
o f fo c a l m y o c y to lic
n e c ro sis,
in te rstitia l
fib ro sis
a n d h y p e rtro p h y
o f th e c irc u m ja c e n t
c a rd ia c m u sc le c e lls.
A p a rt fro m th is, th e h y p o th e sis
h a s b e e n p u t fo rw a rd
th a t
th e in fla m m a to ry
in filtra te
c o n sistin g
p re d o m in a n tly
o f
m a c ro p h a g e s
a n d ly m p h o c y te s
c o n trib u te s
to th e sta te o f
m ic ro v a sc u la r
h y p o p e rfu sio n
o f th e
se c re tio n
o f A 2
th ro m b o x a n
a n d p la te le t
a g g re g a tio n
a n d v e sse l sp a sm .
M ic ro v a sc u la r
sp a sm
a n d m ic ro a n e u rism
fo rm a tio n
in c o ro n a ry
c irc u la tio n
w e re d e sc rib e d
in a c u te
T. cruzi
in fe c tio n
in m ic e (8 ) in a sim ila r m a n n e r to th a t o b se rv e d
in
o th e r
c o n g e stiv e
m y o c a rd io p a th y
(9 ,1 1 ).
T h e se
m ic ro v a sc u la r
c h a n g e s
w e re d e te c te d
e a rly o n d u rin g th e
e v o lu tio n
o f e x p e rim e n ta l
C h a g a s'
d ise a se ,
b e fo re
th e
o n se t o f d e g e n e ra tio n
o r m y o c a rd ia l
fib ro sis.
T o b a c k u p th e m ic ro v a sc u la r
h y p o th e sis
it h a s b e e n
re la te d th a t c h ro n ic a d m in istra tio n
o f V e ra p a m il, a c a lc iu m
-c h a n n e l
b lo c k in g
d ru g , p ro d u c e d
a sig n ific a n t
re d u c tio n
in in fla m m a tio n
a n d m y o c a rd ia l
fib ro sis in
T. cruzi
in fe c te d
m ic e , a p a rt fro m a 1 0 tim e s lo w e r m o rta lity
ra te d u rin g a
7 0 -d a y
o b se rv a tio n
p e rio d
(2 7 ).
V e ra p a m il
a p p a re n tly
m a in ta in s
v a sc u la r
p e rfu sio n
b y
v a so d ila tio n
a s
a
c o n se q u e n c e
o f its a c tio n o n th e sm o o th m u sc le c e lls a n d
b y a n in h ib itin g
e ffe c t o n p la te le t a g g re g a tio n
(4 ).
In vitro
stu d ie s
h a v e
sh o w n
in fe c tio n
re la te d
e n d o th e lia l
c e ll
d y sfu n c tio n
a n d a su b se q u e n t
in c re a se in p la te le t re a c tiv ity
(4 8 ).
In te ra c tio n
b e tw e e n
p la te le ts
a n d
d a m a g e d
e n d o th e liu m
o r th e su b e n d o th e lia l
su rfa c e m a y stim u la te
p la te le t d e riv e d
g ro w th
fa c to r. T h e fin d in g o f h ig h le v e ls
o f A 2 th ro m b o x a n
in a c u te ly
in fe c te d
p la sm a
w o u ld
c o n trib u te
to p la te le t
a g g re g a tio n
in c re a sin g
th e fo c a l
m ic ro v a sc u la r
sp a sm .
R e c e n t sc in tillo g ra p h ic
stu d ie s
u sin g T h a lliu m -2 0
1
in c h ro n ic
d ila te d
c a rd io p a th ic
C h a g a s'
p a tie n ts
h a v e
d e m o n stra te d
a d e c re a se
in m y o c a rd ia l
p e rfu sio n
(1 4 ,2 3 ),
a lik e ly
c o n se q u e n c e
o f m ic ro v a sc u la r
isc h e m ia
(2 9 ).
W ith in th is c o n te x t m y o c a rd ia l p e rfu sio n
d e c re a se h a s b e e n
d e sc rib e d
in 1 5 to 3 0 d a y p o st
T. cruzi
in fe c te d
m ic e ,
ra d io g ra p h ic a lly
e v a lu a te d
u sin g
th e
1 9 Io d in e 3 .3
-d im e th y l-1 8
n o n a d e c e n o ic
fa tty a c id (4 9 ).
THEORY
In th is p re se n t w o rk w e h a v e p re se n te d
a n a lte rn a ti v e
h y p o th e sis
c o n c e rn in g
c h ro n ic
C h a g a s'
m y o c a rd itis
p a th o g e n e sis
d e v e lo p m e n t
is re la te d
to p ro g re ssiv e
a n d
a c c u m u la tiv e
fo c a l
c e llu la r
n e c ro sis,
a sso c ia te d
w ith
d istrib u tiv e
a n d
re a c tiv e
in te rstitia l
fib ro sis
a n d
c irc u m ja c e n t
m y o c y tic
h y p e rtro p h y .
T h e se
p ro c e sse s
a re
in itia te d
a n d p e rp e tu a te d
b y se lf im m u n e
fa c to rs
a n d b y
a lte ra tio n s
to m y o c a rd ia l
m ic ro c irc u la tio n
(F ig . 2 ). T h e
a u to n o m o u s
n e rv o u s
sy ste m 's
in trin sic
a lte ra tio n s
a re
im p lic a te d in th e g lo b a l c o n te x t o f th e c lin ic a l-p a th o lo g ic a l
e v o lu tio n
o f c h ro n ic
C h a g a s'
c a rd io p a th y .
T h e p ro p o se d
p h y sio p a th o g e n ic
m e c h a n ism
w o u ld
im p ly
fu tu re
th e ra p e u tic
stra te g y fo r tre a tin g
c h ro n ic
C h a g a s'
p a tie n ts,
e n h a n c in g
m e d ic a l
c a re
a n d tre a tm e n t
a n d , h o p e fu lly ,
im p ro v in g
p ro g n o sis.
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