SAO PAULO
\L
D a lm o d e S o u z a A m o rim , J o s e A n to n io M a rin N e to
Functional alterations of the autonomic
n e rv o u s sy ste m in C h a g a s' h e a rt d ise a se
Division of Cardiology, Department
of Internal Medicine,
Faculdade de Medicina de Ribeiriio Pre to da
Universidade de Siio Paulo - Siio Paulo, Brazil
S everal independent pathological studies in experim ental m odels and in hum an beings show ed conspicuous autonom ic denervation in C hagas' disease. In spite of the inherently com plex structural organization of the autonom ic nervous system , the
parasym pathetic and sym pathetic divisions are involved, as show n by m any functional studies. H ence, C hagas' disease
represents a unique m odel of im pairm ent of the autonom ic control of the heart, in absence of the nonspecific effects of cardiac failure. A n im portant lim itation of the studies thus far carried out is the lack of a better know ledge of the m olecular biology
characteristics of different strains of T . c ru z i.T his could explain som e geographical discrepancies found in the clinical behaviour of
C hagas' disease, and contribute to a better understanding of its pathophysiology.
U N IT E R M S : C hagas' disease. A utonom ic nervous system .
IN T R O D U C T IO N
S
c o w o r k e r s ,in c e th e p r im o r d ia lth e p a th o lo g ic a ls tu d ie s b y C a r lo sin v o lv e m e n tC h a g a so f th ea n d n e r v o u s s y s te m in th e tr y p a n o s o m ia s is d is c o v e r e d b y h im h a s b e e n th e s u b je c t o f r e s e a r c h a n d s p e c u la tio n ( 1 4 ) . T h e e x is te n c e o f a n e r v o u s f o r m c h a r a c te r iz e d b y c e n tr a l m a n if e s ta tio n s o f n e u r o p a th y , in c lu d in g p s y c h ia tr ic d is o r d e r s , h a s in d e e d b e e n p r o p o s e d ( 7 5 ) ; h o w e v e r , th isA d d re s s fo r c o rre s p o n d e n c e : D a lm o d e S o u z a A m o rim
F a c u ld a d e d e M e d ic in a d e R ib e ira o P re to d a U n iv e rs id a d e d e S a o P a u lo
D iv is a o d e C a rd io lo g ia - D e p a rta m e n to d e C lfn ic a M e d ic a R ib e ira o P re to - S P - B ra s il - C E P 1 4 0 4 9 -9 0 0
f o r m d id n o t r e c e iv e d e f in itiv e c lin ic a l a c c e p ta n c e d e s p ite th e f a c t th a t it w a s s p e c if ic a lly in v e s tig a te d in s tu d ie s u s in g d if f e r e n t m e th o d o lo g ic a l a p p r o a c h e s . N e v e r th e le s s , n o t o n ly it is p o s s ib le . to d e te c t a n a to m ic a lly p o ly f o c a l a g g r e s s io n s a g a in s t th e c e n tr a l n e r v o u s s y s te m , b u t th e r e a r e s tu d ie s d e m o n s tr a tin g a c e r ta in d e g r e e o f s e n s o r im o to r f u n c tio n a l im p a ir m e n t d e te c te d b y la b o r a to r y te s ts in p a tie n ts w ith C h a g a s ' d is e a s e ( 5 7 ,6 7 ) .
T h e r e is a m p le e v id e n c e th a t C h a g a s ' d is e a s e a s c h a r a c te r iz e d b y a m a r k e d p r e f e r e n c e f o r in v o lv e m e n t o f th e m u s c le a n d n e r v o u s s y s te m s ( 3 5 ,3 6 ) . I n th is r e s p e c t, th e p h y s io p a th o lo g y o f s e v e r a l c lin ic a l s y n d r o m e s a s s o c ia te d w ith C h a g a s ' d is e a s e , s u c h a s c a r d io p a th y , e s o p h a g o p a th y , c o lo p a th y e tc ., s h o u ld lo g ic a lly in v o lv e e s s e n tia lly m u s c u la r a n d n e r v o u s le s io n s in th e c o r r e s p o n d in g o r g a n s . T h u s , th e in v o lv e m e n t o f th e n e u r o v e g e ta tiv e s y s te m s e e m s to b e th e e s s e n tia l e le m e n t in th e d ig e s tiv e m a n if e s ta tio n s o f th e d is e a s e , w ith a
F i g u r e 1 . N u m b e r o f g a n g l i o n c e l l s p e r m m o f r i g h t a t r i a l t i s s u e . T h e f u l l l i n e i s t h e a v e r a g e a n d t h e d a s h e d l i n e s a r e t h e s t a n d a r d d e v i a t i o n s f o r f i v e c o n t r o l h e a r t s f r o m a d u l t s a g e d 4 4 . 0 : t 6 . 0 y e a r s . T h e s o l i d c i r c l e s i n d i c a t e i n d i v i d u a l v a l u e s f o r s e v e n p a t i e n t s w i t h d i l a t e d c a r d i o m y o p a t h y , w h i l e t h e o p e n c i r c l e s r e v e a l v e r y l o w n e u r o n a l c o u n t i n t h r e e c h a g a s i c h e a r t s . ( F r o m A m o r i m a n d O l s e n , 1 9 8 21 3
) .
O n th e o th e r h a n d , a lth o u g h th is a tr ia l ( p a r a s y m p a th e tic ) n e u r o n a l d e p o p u la tio n c a n n o t b e c o n s id e r e d a n a ttr ib u te o f C h a g a s ' d is e a s e a lo n e , in a ll c o m p a r a tiv e s tu d ie s w ith o th e r d is e a s e s s u c h a s r h e u m a tis m ( 3 9 ,6 4 ) , e n d o m y o c a r d ia l f ib r o s is ( l 0 ) , d ila te d c a r d io m y o p a th y ( 8 ,1 0 ) a n d h y p e r te n s iv e h e a r t d is e a s e ( 3 9 ) , th e p h e n o m e n o n w a s f o u n d to b e m u c h m o r e c o n s p ic u o u s in C h a g a s ' h e a r t d is e a s e ( F ig . 1 ) . A n o th e r im p o r ta n t f e a tu r e o f th e p a r a s y m p a th e tic n e u r o n a l d e p o p u la tio n o f c h a g a s ic e tio lo g y is th e a b s e n c e o f a c o r r e la tio n b e tw e e n th e in te n s ity o f d e n e r v a tio n a n d o th e r c a r d ia c a n a to m o p a th o lo g ic a l c h a r a c te r is tic s ( 1 5 ) , th e ty p e o f d e a th ( s u d d e n , d u r in g c a r d ia c f a ilu r e ) ( 4 0 ) o r th e c lin ic a l p h a s e ( f o r m ) o f th e d is e a s e a t th e tim e o f d e a th ( 4 1 ) . A s a n e x c e p tio n to th is r u le , o n ly w ith r e s p e c t to th e c o n c o m ita n c e o f d ig e s tiv e in v o lv e m e n t ( m e g a e s o p h a g u s a n d /o r m e g a c o lo n ) , a s ig n if ic a n t c o r r e la tio n w ith th e in te n s ity o f c a r d ia c p a r a s y m p a th e tic d e p o p u la tio n h a s b e e n r e c o r d e d ( 2 ) .
A p p a r e n tly , it w a s o n ly in a s y s te m a tic s tu d y o f th e c a r d ia c p a r a s y m p a th e tic n e r v o u s s y s te m c a r r ie d o u t in p r e d o m in a n c e o f th is m e c h a n is m o v e r th e c o n c o m ita n t
d ir e c t m y o p a th ic p r o c e s s in th e e s o p h a g u s a n d c o lo n ( 3 6 ,5 2 ) .
H o w e v e r , th e m e c h a n is m s r e s p o n s ib le f o r tr ig g e r in g a n d in s ta lla tio n o f th e m u s c u la r a n d n e r v o u s le s io n s d e te c te d d u r in g th e a c u te a n d c h r o n ic p h a s e s o f th e d is e a s e h a v e n o t b e e n s u f f ic ie n tly c la r if ie d . F u r th e r m o r e , th e p h y s io p a th o lo g ic a l r o le o f th e n e r v o u s le s io n s d o c u m e n te d in C h a g a s ' d is e a s e c o n tin u e s to b e c o n tr o v e r s ia l, e s p e c ia lly w ith r e s p e c t to C h a g a s ' h e a r t d is e a s e .
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A G G R E S S I O N A G A I N S T T H E
P A R A S Y M P A T H E T I C S Y S T E M O F T H E
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O n th e b a s is o f th e r e s u lts o b ta in e d in a u to p s y s tu d ie s a t s e v e r a l in d e p e n d e n t c e n te r s , it is p o s s ib le to c o n c lu d e th a t le s io n s o f th e in tr a c a r d ia c n e r v o u s s y s te m a r e p r a c tic a lly c o n s ta n t in h u m a n tr y p a n o s o m ia s is o c c u r r in g in B r a z il ( 3 5 ,3 6 ,5 4 ,5 5 ) . T h e s e le s io n s d if f u s e ly in v o lv e th e c a r d ia c n e r v o u s s tr u c tu r e s , a lth o u g h th e y a r e c h a r a c te r iz e d b y th e ir p e c u lia r f o c a l n a tu r e o f ir r e g u la r a n d u n p r e d ic ta b le d is tr ib u tio n . S y s te m a tic e v a lu a tio n s u s in g lig h t a n d e le c tr o n m ic r o s c o p y h a v e d e m o n s tr a te d d e g e n e r a tiv e le s io n s in s u b p e p ic a r d ia l g a n g lia , in S c h w a n n a n d s a te llite c e lls , a n d in m y e lin ic a n d a m y e l! n ic n e r v e f ib e r s d e e p in s id e th e m y o c a r d iu m ( 5 4 ,7 2 ) .
I n o r d e r to q u a n tif y th e e x te n t o f p a r a s y m p a th e tic d e n e r v a tio n in th e c h a g a s ic h e a r t, K 6 b e r le a n d c o lla b o r a to r s a d o p te d , s ta r tin g in th e 1 9 5 0 's , te c h n iq u e s o f n e u r o n a l c o u n tin g b a s e d o n e x h a u s tiv e a n d s ta n d a r d iz e d m ic r o s c o p ic e x p lo r a tio n o f s e r ia l h is to lo g ic a l s e c tio n s o b ta in e d f r o m th e s o - c a lle d in te r c a v a l a tr ia l b a n d ( 8 ,3 6 ,5 5 ) . T h is m e th o d p e r m itte d th e d e f in ite d e te c tio n o f c a r d ia c n e u r o n d e p o p u la tio n in a u to p s ie d c h a g a s ic s . D if f e r e n t q u a n tita tiv e m e th o d s e x p lo r in g o th e r a n a to m ic a l r e g io n s o f th e h e a r t a d o p te d b y in d e p e n d e n t r e s e a r c h e r s c o n f ir m e d th e in d is p u ta b le r e d u c tio n o f a tr ia l in tr a m u r a l n e u r o n s in in d iv id u a ls w h o h a d d ie d d u r in g d if f e r e n t p h a s e s , o r w ith d if f e r e n t f o r m s o f C h a g a s ' d is e a s e ( 4 2 ,5 4 ,6 4 ,7 2 ) . S in c e th e b e g in n in g , e x tr e m e v a r ia b ility in in d iv id u a l n e u r o n a l c o u n ts w a s o b s e r v ~ d in a u to p s ie d c h a g a s ic s . T h e r e w e r e c a s e s in w h ic h d e s tr u c tio n a p p e a r e d to b e to ta l ( n o t a s in g le in ta c t n e u r o n w a s f o u n d ) , s id e b y s id e w ith c a s e s in w h ic h th e n u m b e r o f n e r v o u s c a r d ia c c e lls w a s w ith in th e lim its . u s u a lly d e te c te d in " n o r m a l" c o n tr o ls ( 5 4 ,7 2 ) .
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V e n e z u e la (7 0 ), th a t th e p h e n o m e n o n o f n e u ro n a l d e p o p u la tio n in a u to p s ie d c h a g a s ic s w a s d e n ie d . A c c o rd in g to th a t s tu d y , th e re m a y b e a m ild fib e r d e g e n e ra tio n w ith o u t a s ig n ific a n t re d u c tio n in n u m b e r o f n e u ro n s . It s h o u ld b e p o in te d o u t th a t, a t le a s t w ith re s p e c t to q u a n tita tiv e a s p e c ts , th e s e in v e s tig a to rs p ro b a b ly m a d e th e m is ta k e o f c o u n tin g o n ly g a n g lia a n d n o t a c tu a l n e u ro n s . O th e r p o s s ib ilitie s th a t m a y e v e n tu a lly e x p la in th is d is c re p a n c y b e tw e e n th e s tu d y in q u e s tio n a n d th e o th e rs w ill b e a n a ly z e d fu rth e r o n .
T h e e x p e rim ~ n ta l s tu d ie s c a rrie d o u t o n v a rio u s a n im a l m o d e ls o f la b o ra to ry in fe c tio n w ith
T. cruzi
m a y b e c o n s id e re d to c o n firm q u a lita tiv e ly a n d q u a n tita tiv e ly th e a g g re s s io n o f c h a g a s ic e tio lo g y a g a in s t th e in tra c a rd ia c n e rv o u s s tru c tu re (2 2 ,7 1 ). H o w e v e r, tw o a d d itio n a l re le v a n t a s p e c ts e m e rg e fro m th e s e s tu d ie s : a ) e le c tro n m ic ro s c o p y a n d h is to c h e m ic a l te c h n iq u e s d e m o n s tra te th e g e n e ra liz e d o c c u rre n c e o f p a th o lo g ic a l in v o lv e m e n t o f a tria l c a rd ia c n e rv o u s s tru c tu re in te rm s o f a n a to m ic a l a n d fu n c tio n a l d a m a g e in a c u te ly in fe c te d m ic e (7 1 ); b ) th e p o te n tia l fo r a g g re s s io n a g a in s t c a rd ia c g a n g lio n ic s tru c tu re s a n d m y e n te ric n e rv o u s p le x u s e s a p p e a rs s tro n g ly to d e p e n d o n th e p a ra s ite s tra in u s e d to p ro d u c e c h a g a s ic in fe c tio n a n d o n its p a rtic u la r in te ra c tio n w ith th e in o c u la te d h o s t (6 5 ). T o illu s tra te , in s tu d ie s o n c h ro n ic in fe c tio n in m ic e , th e Y s tra in p ro v e d to b e m u c h m o re p a th o g e n ic fo r th e c o lo n ic A u e rb a c h p le x u s th a n th e C o lo m b ia s tra in , a n d th e n e u ro n -d a m a g in g p o te n tia l o f th e B e re n ic e s tra in a p p e a re d to b e g re a te r th a n th a t o f th e A B C s tra in , w h e re a s s tra in s is o la te d in th e re g io n o f th e B ra z ilia n B a h ia n " R e c o n c a v o " s e e m to p re s e n t lo w v iru le n c e a g a in s t th e n e rv o u s s tru c tu re s o f th e d ig e s tiv e tu b e (9 ). In a n o th e r s tu d y , th e Y a n d B o liv ia s tra in s s h o w e d g re a te r n e u ro n -d e s tro y in g a b ility th a n th e P F s tra in (6 5 ).c a u s e d th e p a ra d o x ic a l e ffe c t o f re d u c in g th e n u m b e r o f a u ric u la r b e a ts " (1 4 ).
In 1 9 5 5 , A . B ra s il a g a in p o in te d o u t, a s p a rt o f th e s o -c a lle d " a u to n o m ic s in o a tria l b lo c k a d e " , th e in e ffe c tiv e n e s s o f a tro p in e in in d u c in g ta c h y c a rd ia in c h ro n ic c h a g a s ic p a tie n ts (1 2 ).
A m o n g th e s e o rig in a l s tu d ie s w e re th o s e o n th e p a rtic ip a tio n o f n o n s p e c ific m e c h a n is m s o f d e p re s s io n o f c a rd ia c v a g a l c o n tro l lin k e d to c a rd ia c fa ilu re o f a n y e tio lo g y (1 7 ,2 9 ). S ta rtin g in th e 1 9 6 0 's , a n e x te n s i v e s e rie s o f s tu d ie s w a s u n d e rta k e n in th e L a b o ra to ry o f C a rd ia c C a th e te riz a tio n o f th e F a c u lty o f M e d ic in e o f R ib e ira o P re to . T h e s tu d ie s w e re c a rrie d o u t o n c h a g a s ic p a tie n ts c a re fu lly s e le c te d o n th e b a s is o f th e a b s e n c e o f c u rre n t o r p re v io u s m a n ife s ta tio n s o f h e a rt fa ilu re a n d d e m o n s tra te d th a t c h ro n ic c h a g a s ic p a tie n ts s h o w :
a ) a n a b n o rm a l re s p o n s e to p h a rm a c o lo g ic a l in h ib itio n o f th e e ffe re n t c a rd ia c p a ra s y m p a th e tic s y s te m (n o n -e v o k e d s in u s ta c h y c a rd ia , lik e in n o rm a l in d iv id u a ls , b y in tra v e n o u s a tro p in e a d m in is tra tio n ) (5 ,4 8 ) (F ig . 2 ).
b ) A b n o rm a l re s p o n s e to re fle x in h ib itio n b y p h y s io lo g ic a l s tim u li o f th e e ffe re n t c a rd ia c p a ra s y m p a th e tic s y s te m (d e fic ie n t s in u s ta c h y c a rd ia c re s p o n s e d u rin g th e p h a s e o f h y p o te n s iv e c o m p re s s io n o f th e V a ls a lv a m a n e u v e r (4 4 ), a t lo w -in te n s ity le v e ls o f
H E A R T R A T E R E S P O N S E S T O A T R O P IN E 0 .0 4 m g lk g IV
F ig u r e 2 . E f f e c t s o f a t r o p in e s u lf a t e o n h e a r t r a t e ( p e r ip h e r a l
v e n o u s a d m in is t r a t io n a t t h e d o s e o f 0 . 0 4 m g p e r k ilo ) . V a lu e s
p r io r t o ( C ) a n d f o llo w in g v a g a l b lo c k a d e ( A ) . A b s o lu t e v a lu e s
( le f t p a n e l) a n d in d iv id u a ls c h a n g e s ( r ig h t p a n e l) . ( F r o m M a r in
-N e t o e t a I . , 1 9 8 63 3 ) .
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P A R A S Y M P A T H E T I C C A R D I A C D A M A G E
T h e o rig in a l p a p e rs b y C a rlo s C h a g a s a n d c o lla b o ra to rs m e n tio n a p e c u lia r a b s e n c e o f th e c h ro n o tro p ic re s p o n s e to th e v a g o ly tic a g e n t a tro p in e in c h a g a s ic p a tie n ts : " O n th e b a s is o f a la rg e n u m b e r o f c a s e s , w e c o n c lu d e th a t th e d ro m o tro p ic a c tio n o f th is d ru g is q u ite c o n s id e ra b le a n d th a t its h a b itu a l c h ro n o tro p ic a c tio n is v e ry s m a ll in m a n y c a s e s " . " In th e p re s e n c e o f c o m p le te b lo c k a d e , th e d ro m o tro p ic a c tio n o f th e d ru g w a s a b s e n t. In th e s a m e c a s e s , th e c h ro n o tro p ic a c tio n w a s o f lo w in te n s ity a n d w a s o fte n in th e n e g a tiv e d ire c tio n , i.e ., it
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c o n t i n u o u s d y n a m i c e f f o r t w i t h p r o g r e s s i v e l o a d s ( 2 6 ) , i m m e d i a t e l y a f t e r p a s s i v e a l t e r a t i o n o f b o d y p o s i t i o n ( 4 7 ,4 8 ) , d u r i n g t h e e x e c u t i o n o f a n i s o m e t r i c e f f o r t ( 4 7 ) ( F i g . 3 ) a n d d u r i n g t h e e a r l y m o m e n t s o f c h r o n o t r o p i c a d j u s t m e n t a t e a c h p h a s e o f a d y n a m i c e f f o r t w i t h a d i s c o n t i n u o u s p r o t o c o l o f i n c r e a s i n g i n t e n s i t y ( 2 8 ) .
c ) A b n o r m a l r e s p o n s e t o r e f l e x e x c i t a t i o n o f t h e c a r d i a c e f f e r e n t v a g a l c o m p o n e n t b y p h a r m a c o l o g i c a l m e a n s ( a b s e n c e o f s i n u s b r a d y c a r d i a d u r i n g s y s t e m i c a r t e r i a l h y p e r t e n s i o n p r o v o k e d b y i n f u s i o n o f m e t a r a m i n o l ( F i g . 4 ) a n d b y i n t r a v e n o u s i n j e c t i o n s o f p h e n y l e p h r i n e ) ( 5 ,3 3 ) ( F i g . 5 ) .
d ) A b n o r m a l r e s p o n s e t o r e f l e x s t i m u l a t i o n o f t h e c a r d i a c e f f e r e n t p a r a s y m p a t h e t i c c o m p o n e n t b y p h y s i o l o g i c a l m e t h o d s ( a b s e n c e o f s i n u s b r a d y c a r d i a d u r i n g s y s t e m i c a r t e r i a l h y p e r t e n s i o n i n d u c e d i n t h e d e c o m p r e s s i o n p h a s e o f t h e Y a l s a l v a m a n e u v e r ( 4 4 ) , o r b y h e a d d o w n p o s i t i o n i n g f r o m a n u p r i g h t p o s i t i o n ( 4 7 ) , a n d d u r i n g t h e r e f l e x s t i m u l u s c a u s e d b y f a c e i m m e r s i o n ) ( 2 5 ) .
e ) R e d u c t i o n o f t h e m a g n i t u d e o f s i n u s a r r h y t h m i a d e p e n d i n g o n t h e r e s p i r a t o r y c y c l e a c c o r d i n g t o a r i g o r o u s l y s t a n d a r d i z e d m e t h o d b a s e d o n s y s t e m a n a l y s i s t e c h n i q u e s ( 2 7 ,5 0 ) .
f ) S i g n i f i c a n t d e c r e a s e o f t h e p o t e n c y o f n i g h t a n d m o r n i n g c h r o n o t r o p i c v a r i a b i l i t y o f b o t h t h e l o w - f r e q u e n c y a n d h i g h - f r e q u e n c y c o m p o n e n t s , d e m o n s t r a t e d b y s p e c t r a l a n a l y s i s o f t h e e l e c t r o c a r d i o g r a p h i c H o l t e r r e c o r d i n g ( 1 8 ,1 9 ) ( F i g . 6 ) .
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s u b je c ts ( N ) , c h a g a s ic p a tie n ts w ith th e d ig e s tiv e p a th o lo g y ( 0 ) a n d p a tie n ts w ith c h r o n ic C h a g a s ' h e a r t d is e a s e . B o th g r o u p s o f p a tie n ts h a d lo w e r c h r o n o tr o p ic r e s p o n s e s ( b e a ts /m in ) p e r m a x im a l v o lu n ta r y c o n tr a c tio n . ( F r o m S o u s a , A C S e t a I., 1 9 8 76 6 ) .
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5 . B a r o r e c e p tp r s e n s itiv ity ( 8 ) e v a lu a te d b y c h a n g e s in s y s te m ic a r te r ia l p r e s s u r e r e la te d to s u b s e q u e n t R - R in te r v a ls , fo llo w in g p e r ip h e r a l v e n o u s a d m in is tr a tio n o f p h e n y le p h r in e . A s c o m p a r e d to th e c o n tr o l s u b je c t, th e b a r o r e c e p to r s e n s itiv ity is d e p r e s s e d in th e c h a g a s ic p a tie n t.•
T h e s y m p a th e tic s y s te m h a s b e e n s tu d ie d m u c h le s s e x te n s iv e ly th a n th e p a r a s y m p a th e tic s y s te m in C h a g a s ' d is e a s e .
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in f e c tio n p r e c e d e d th e d e te c tio n o f le s io n s o f a d r e n e r g ic s tr u c tu r e s in a u to p s ie d h u m a n s . I t f ir s t a p p e a r e d th a t n o n u m e r ic a l n e u r o n a l r e d u c tio n o c c u r r e d in th e s o la r p le x u s o f c h r o n ic c h a g a s ic r a ts ( 2 1 ) . S e v e r a l in d e p e n d e n t in v e s tig a tio n s la te r r e p o r te d s y m p a th e tic d e n e r v a tio n in c h a g a s ic a n im a ls w ith la b o r a to r y in f e c tio n in th e a c u te a n d c h r o n ic p h a s e s o f in f e c tio n w ith th e Y s tr a in . T h is d e n e r v a tio n w a s d e te c te d in m ic e ( 2 4 ,7 4 ) , in th e in f e r io r h y p o g a s tr ic p le x u s o f r a ts ( 1 6 ) , a n d in th e ju x ta p r o s ta tic p le x u s o f g u in e a p ig s ( 2 3 ) . A g a in , th e ty p e o f s tr a in u s e d s e e m s to p la y a d e c is iv e r o le in th e tr ig g e r in g o f n e u r o n a l le s io n s , w ith d if f e r e n t d e g r e e s o f p a r a s itic tr o p is m h a v in g b e e n c h a r a c te r iz e d f o r th e s e s tr u c tu r e s . A g g r e s s io n o f c h a g a s ic e tio lo g y a g a in s t th e s y m p a th e tic s y s te m w a s a n a to m ic a lly d o c u m e n te d in a u to p s y m a te r ia l in th e e a r ly 1 9 7 0 's ( l) . A m e a n 3 7 % d e p o p u la tio n w a s d e te c te d in th e c e r v ic a l- th o r a c ic g a n g lia , w h ic h a r e in d e e d th o s e th a t p r o je c t s y n a p s e s to w a r d s th e h e a r t. I t s h o u ld b e p o in te d o u t th a t th e p a r a s y m p a th e tic d e n e r v a tio n d e te c te d in th e s a m e c h a g a s ic c a d a v e r s w a s o f th e o r d e r o f 5 2 % .ANATOMICAL
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T h e a b o v e r e s u lts a r e c o n s is te n t w ith th o s e o b ta in e d in s tu d ie s c o n d u c te d in C o r d o b a , A r g e n tin a , s in c e th e
1 9 7 0 's u s in g m e th o d s s u c h a s Y a ls a lv a m a n e u v e r , in je c tio n o f p h e n y le p h r in e , p a s s iv e p o s tu r a l a lte r a tio n , a c u te a tr o p in iz a tio n , a n d q u a n tif ic a tio n o f r e s p ir a to r y s in u s a r r h y th m ia ( 1 3 ,6 1 ) . A c c o r d in g to th e s tu d ie s p u b lis h e d in th e lite r a tu r e , o n ly th e in v e s tig a tio n c o n d u c te d in P a n a m a d id n o t d e te c t d y s f u n c tio n o f c a r d ia c p a r a s y m p a th e tic c o n tr o l in C h a g a s ' d is e a s e ( 3 1 ) .
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A f u n c tio n a l in v o ly e m e n t o f th e c a r d ia c s y m p a th e tic s y s te m w a s f ir s t s u s p e c te d in s tu d ie s in w h ic h d e f ic ie n t r e f le x ta c h y c a r d ia w a s d e te c te d in th e p r e s e n c e o f s y s te m ic a r te r ia l h y p o te n s io n . A lth o u g h th e s e c h r o n o tr o p ic d e f ic ie n c ie s w e r e f ir s t d e m o n s tr a te d in p a tie n ts w ith C h a g a s ' h e a r t d is e a s e w ith a h is to r y o f h e a r t f a ilu r e , th e y w e r e la te r d e te c te d a ls o in th e a b s e n c e o f s u c h a h is to r y ( 4 4 ) . I t s h o u ld b e p o in te d o u t th a t, w h e n p a r a s y m p a th e tic d e n e r v a tio n o c c u r s , d e f ic ie n t r e f le x ta c h y c a r d ia d u r in g a tr a n s ito r y p e r io d o f a r te r ia l s y s te m ic h y p o te n s io n c a n n o t b e im p u te d to d e p r e s s io n o f th e a d r e n e r g ic s y s te m : u n d e r s u c h c ir c u m s ta n c e s th e r e m a y b e r e d u c e d ta c h y c a r d ia d u r in g th e c o m p r e s s io n p h a s e o f th e Y a ls a lv a m a n e u v e r
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F ig u r e - S . T w e n t y - f o u r h o u r s s p e c t r a l v a r ia b ilit y o f c a r d ia c r a t e r e c o r d e d in c o n t r o l s u b je c t s ( N R ) a n d in c h r o n ic c h a g a s ic p a t ie n t s
( N A ) . M e a n a n d s t a n d a r d d e v ia t io n f o r t h e t w o g r o u p s . H a t c h e d a n d b lo c k b a r s in d ic a t e s le e p in g ( n ig h t im e ) a n d a w a k e n e d ( d a y t im e )
v a lu e s , r e s p e c t iv e ly . C lo c k w is e f r o m u p p e r le f t : T P ( t o t a l p o w e r ) , L F P ( lo w f r e q u e n c y p o w e r ) , H F P ( h ig h f r e q u e n c y p o w e r ) a n d L F / H F
( r a t io lo w / h ig h f r e q u e n c y ) . C h a g a s ic p a t ie n t s s h o w e d lo w e r v a lu e s t h a n n o r m a ls , in a d d it io n t o t h e la c k o f e x p e c t e d L F / H F r a t io
a w a k e n in g . ( F r o m E n d in , M , e t a i, 1 9 9 24 1).
o r d u rin g in h alatio n o f am y l n itrite b ecau se th ere is n o p arasy m p ath etic to n u s to b e lib erated in a reflex m an n er, an d th e ch ro n o tro p ic resp o n se w ill th en d ep en d ex clu siv ely o n sy m p ath etic stim u latio n , in ev itab ly b eco m in g o f sm aller m ag n itu d e (4 5 ).
O n th e o th er h an d , in early an d recen t stu d ies o n ch ag asic p atien ts w ith v ario u s fo rm s o f th e d isease b u t w ith n o card iac failu re, n o d eficien cy o f ad ren erg ic resp o n se to d y n am ic p h y sical ex ercise w as d etected (2 6 ,2 8 ). A lo ss in th e lin earity o f th e ch ro n o tro p ic resp o n se o n ly o ccu rs at lo w -in ten sity ex ercise lev els, p red o m in an tly co n sistin g o f rem o v al o f th e in h ib ito ry v ag al to n ic effect o n th e sin u s n o d e (2 6 ). W ith h ig h er w o rk lo ad s, th e in crease in h eart rate p ro v o k ed b y d y n am ic ex ercise in ch ag asic p atien ts b ecam e su p erim p o sab le to th at o f n o rm al in d iv id u als, th u s p rev en tin g th e d em o n stratio n o f sy m p ath etic d ep ressio n in C h ag as' d isease b y th is m eth o d .
H o w ev er, fo llo w in g in th e p ath first in d icated b y C arlo s C h ag as th e test o f p assiv e ch an g es o f b o d y p o sitio n w as u sed to ev alu ate th e card iac sy m p ath etic sy stem (4 5 ,4 6 ,4 7 ). It w as first o b serv ed th at th e elev atio n in h eart rate ev o k ed b y th e stan d in g p o sitio n is in d eed b ip h asic: th e in itial resp o n se o ccu rrin g d u rin g th e first few seco n d s d ep en d s o n th e lib eratio n o f th e sin u s n o d e fro m th e v ag al in h ib itio n p resen t in th e su p in e p o sitio n . A fter a few m in u tes in th e u p rig h t p o sitio n , th e h eart rate co n tin u es to
b e h ig h p red o m in an tly b y ad ren erg ic stim u latio n o f th e sin u s n o d e (4 6 ). T h e stan d in g resp o n ses o b serv ed in a g ro u p o f n o rm al in d iv id u als w ere co m p ared to th o se o f a ch ag asic g ro u p in th e co n tro l co n d itio n an d after selectiv e b lo ck ad e o f th e p arasy m p ath etic sy stem w ith atro p in e an d o f th e sy m p ath etic co m p o n en t w ith p ro p ran o lo l. C h ag asic p atien ts w ith p arasy m p ath etic d ep ressio n p resen t a clearly im p aired in itial resp o n se b o th in th e co n tro l co n d itio n an d after ab o litio n o f th e ad ren erg ic sy stem b y b lo ck ad e w ith p ro p ran o lo l. W ith th e v ag al sy stem ab o lish ed b y th e actio n o f atro p in e, th e in itial resp o n ses b eco m e p red ictab ly id en tical an d d ep ressed in b o th g ro u p s. A s to th e d elay ed ad ren erg ic-d ep en d en t effect, ch ag asic p atien ts can b e d istin g u ish ed fro m n o rm al in d iv id u als b o th in th e co n tro l co n d itio n an d after atro p in e b lo ck ad e: w ith th e v ag al m ech an ism b lo ck ed in b o th g ro u p s, th e p ersisten ce o f d iscrim in atio n can o n ly b e u n eq u iv o cally im p u ted to d ep ressio n o f th e ad ren erg ic m ech an ism o f sin u s n o d e co n tro l p resen t in p atien ts w ith C h ag as' h eart d isease (4 6 )
(F ig . 7 ). .
In th e stu d ies cited ab o v e, it w as n ev er p o ssib le to d etect ab n o rm alities related to au to n o m ic v ascu lar co n tro l. In o th er w o rd s, th e b eh av io r o f sy stem ic arterial p ressu re in resp o n se to th e ad m in istratio n o f ag en ts th at red u ce o r elev ate v ascu lar resistan ce d u rin g d y n am ic o r iso m etric p h y sical effo rt, d u rin g th e ex ecu tio n o f th e V alsalv a
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m aneuver and even during passive postural tests, could never be distinguished in a statistically significant m anner betw een chagasic patients and norm al controls (5,33).
H ow ever, even w ith the use of tilting tests and, m ore recently, of the hyperventilation test, studies carried out in C ordoba, A rgentina, have dem onstrated patterns of diastolic pressure response differing from those observed in norm al controls and com patible w ith the presence of a certain degree of sym pathetic cardiovascular dysfunction in chagasic patients (32,59). A ccording to these studies, the deficient adrenergic vasom otor regulation, taken together w ith frequently reduced levels of basal heart rate, m ay explain the significantly low er system ic tension levels detected in the chagasic population w hen com pared to norm al groups (60).
It should be em phasized that, in contrast to w hat occurs in other disorders w ith generalized involvem ent of the neurovegetative'system (for exam ple, diabetes m ellitus (21), A ndrade am yloidosis (24) etc., in C hagas' disease there is no true clinical syndrom e of cardiovascular dysautonom y w ith standing hypotension, intolerance of dynam ic physical effort, or the characteristic pattern of pressor response to the Y alsalva m aneuver.
T he discrepant features obtained in the investigations discussed above clearly illustrate the difficulty inherent in obtaining m ore in-depth know ledge about the physiopathology of the sym pathetic system in general and in C hagas' disease in particular. Indeed, the structural organization of this autonom ic division itself is
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intrinsecally m ore com plex than that of the parasym pathetic com ponent, w ith the sym pathetic chain presenting an extensive diffusion of ganglionic and postganglionic internuncial connections. T he sym pathetic ganglionic neurons (in contrast to the parasym pathetic ones that are lodged deeply inside the innervated organ), are located at a distance and branch out w idely, w ith their interconnections w ith other neurons and w ith m any receptors being characterized by countless postganglionic fibers. In contrast, the parasym pathetic anatom ical arrangem ent depends on a discrete degree of branching, w ith a proposed basic schem e of neurons selectively connected w ith each receptor by postganglionic fibers separately linked to the synaptic plate. F urtherm ore, the cholinergic m ediator m ust obligatorily act at the site of release since the catalytic system of cholinesterase has a rapid and intense inactivating effect. C onversely, despite the presence of cellular and extracellular enzym es such as C O M T and M A O , the adrenergic m ediators circulate at concentrations sufficient to perm it an im portant action at a distance from their site of release. T hese distinctive characteristics of both system s m ay explain the greater facility in detecting evidence of parasym pathetic function than evidence of depression of the sym pathetic com ponent in C hagas' disease, a disorder know n to induce diffuse dam age to the autonom ic system .
W e m ay speculate, for exam ple, that the use of dynam ic exercise, by representing very intense activity capable of inducing very strong and diffuse stim ulation of
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F ig u r e 7 . C h r o n o t r o p ic r e s p o n s e s d u r in g p a s s iv e c h a n g e s in b o d y p o s it io n ( " t ilt in g t e s t " ) r e c o r d e d in n o r m a ls ( o p e n b a r s ) a n d c h a g a s ic
p a t ie n t s ( h a t c h e d b a r s ) , u n d e r c o n t r o l s it u a t io n a n d f o llo w in g in t r a v e n o u s a d m in is t r a t io n o f a t r o p in e s u lf a t e ( 0 . 0 4 m g / k g a n d p r o p r a n o lo l
( 0 . 2 m g / k g ) . U p p e r p a n e l s h o w s c h a n g e s a t 1 0 s e c o n d s ( v a g a l in h ib it io n ) ; t h e b o t t o m p a n e l s h o w s a lt e r a t io n s a t 1 0 m in u p r ig h t
p o s it io n ( s y m p a t h e t ic in d u c e d ) . I t is t o b e n o t e d t h e s y m p a t h e t ic - in f lu e n c e d h e a r t r a t e r e s p o n s e s in t h e c h a g a s ic p a t ie n t s . ( F r o m
M a r in - N e t o J A e t a i, 1 9 8 63 3).
th e e n tir e c a r d io v a s c u la r a d r e n e r g ic s y s te m a n d f a v o r in g th e in s ta lla tio n o f v e r y h ig h le v e ls o f c ir c u la tin g c a te c h o la m in e s , m a y b e le s s a p p r o p r ia te th a n th e tiltin g te s t to e x p lo r e c a r d ia c p a r a s y m p a th e tic d e n e r v a tio n . U s in g th is le s s e x a c tin g te s t, it w a s p o s s ib le to d e m o n s tr a te a d r e n e r g ic d y s f u n c tio n o f s in u s c o n tr o l ( 4 6 ) , a v o id in g th e m a s k in g o f p o s s ib ly in v o lv e d f o c a l le s io n s b y th e c o m p e n s a tio n o b ta in e d w ith th e d if f u s e r e s p o n s e o f th e s y m p a th e tic s y s te m , a s is th e c a s e f o r d y n a m ic e x e r c is e . S im ila r ly , th e a tte n u a tio n o f th e lo w - f r e q u e n c y c o m p o n e n t d u r in g s p e c tr a l a n a ly s is o f c h r o n o tr o p ic v a r ia b ility in c h a g a s ic p a tie n ts is c o n s is te n t w ith th e o c c u r r e n c e o f s y m p a th e tic d e p r e s s io n ( 1 9 ) ( F ig . 6 ) .
PATHOLOGICAL
SIGNIFICANCE
OF
CARDIOVASCULAR
AUTONOMIC
DYSFUNCTION
W ith th e e x c e p tio n s m e n tio n e d e a r lie r , th e p a th o lo g ic a l in v o lv e m e n t o f th e c a r d io v a s c u la r n e u r o v e g e ta tiv e s y s te m in C h a g a s ' d is e a s e m a y b e c o n s id e r e d to b e a r e c o g n iz e d f a c t o n th e b a s is o f th e r e s u lts o b ta in e d in m a n y s tu d ie s c a r r ie d o u t in d e p e n d e n tly . H o w e v e r , its p h y s io p a th o lo g ic a l r o le in th e tr ig g e r in g o f c h r o n ic C h a g a s ' h e a r t d is e a s e c o n tin u e s to b e c o n tr o v e r s ia l. T h is s itu a tio n is in c o n tr a s t to th e d a ta o b ta in e d in th e s tu d y o f d ig e s tiv e c h a g a s ic le s io n s w h ic h h a v e le d to th e r e c o g n itio n o f th e o b lig a to r y n a tu r e o f d e n e r v a tio n a s th e m a jo r , if n o t th e e x c lu s iv e , p a th o g e n e tic f a c to r o f m e g a e s o p h a g u s a n d m e g a c o lo n ( 9 ,3 5 ,5 2 ) . T h e p h y s io p a th o g e n y o f C h a g a s ' h e a r t d is e a s e is d e f in ite ly m o r e c o m p le x , p e r h a p s a ls o b e c a u s e th e h e a r t is a m u c h m o r e p h y lo g e n e tic a lly e v o lv e d o r g a n w ith c o n s e q u e n t m u c h m o r e e la b o r a te s tr u c tu r e a n d f u n c tio n .
A s a n e x a m p le o f th e d if f ic u lty in c h a r a c te r iz in g th e r e a l im p o r ta n c e o f a u to n o m ic d y s f u n c tio n in c h r o n ic C h a g a s ' h e a r t d is e a s e , it s h o u ld b e e m p h a s iz e d th a t, in c o n tr a s t to w h a t o c c u r s in d ig e s tiv e tr a c t d is e a s e ( 5 2 ) , it h a s n o t b e e n p o s s ib le to d e m o n s tr a te c o n v in c in g ly in h u m a n s th e p r e s e n c e o f a s ta te o f d e n e r v a tio n h y p e r s e n s itiv ity to th e c h o lin e r g ic a g e n t, a s p r e d ic te d b y th e C a n n o n la w , d e s p ite s o m e r e s u lts s u g g e s tin g th is a n o m a ly in
T.
c r u z i- in f e c te d r a ts s u b m itte d to a d m in is tr a tio n o f m e ta c h o lin e a n d to e le c tr ic v a g a l s tim u la tio n ( 3 7 ) .T h e in itia l th e o r y , f o u n d e d o n a n a to m ic a l o b s e r v a tio n s , o f h e a r t d is e a s e w ith d e c r e a s e d p a r a s y m p a th e tic a c tiv ity ( 3 4 ,3 5 ) , im p ly in g a c o n s ta n t
Sao Paulo Medical Journal/RPM 113(2) Mar/Apr 1995
f u n c tio n a l p r e d o m in a n c e o f th e s y m p a th e tic d iv is io n , m e t th e f o llo w in g a p p a r e n tly in s o lu b le c o n c e p tu a l o b s ta c le s : a ) it is n o t p o s s ib le , e v e n in e x p e r im e n ta m o d e ls , to d e m o n s tr a te r e la tiv e o r a b s o lu te a d r e n e r g ic h y p e r a c tiv ity ( 2 6 ,4 5 ,4 6 ) ; b ) in c o n tr a s t, s y m p a th e tic d e n e r v a tio n o c c u r s in C h a g a s ' d is e a s e , e v e n th o u g h le s s in te n s e ly , a s d e te r m in e d a n a to m ic a lly ( 1 ) a n d f u n c tio n a lly ( 4 6 ) ; c ) h e a r t d is e a s e c lin ic a lly m a n if e s tin g a s m y o c a r d ia l d y s f u n c tio n a n d d is o r d e r s o f g e n e r a tio n a n d c o n d u c tio n o f e le c tr ic s tim u li is d e te c te d in r e g io n s w h e r e th e d is e a s e is a p p a r e n tly c a u s e d b y p a r a s ite s tr a in s r e la tiv e ly d e v o id o f n e u r o tr o p is m ( 9 ,3 1 ,7 0 ) ; d ) e v e n in e n d e m ic a r e a s w h e r e d e n e r v a tio n is c le a r ly d e te c ta b le , th e r e is n o s ig n if ic a n t c o r r e la tio n b e tw e e n its f u n c tio n a l e x p r e s s io n a n d th e p r e s e n c e o f d y s r h y th m ia a n d /o r m y o c a r d ia l d e p r e s s io n . O n th is b a s is , th e r e a r e in te n s e ly d e n e r v a te d p a tie n ts w ith n o r m a l c o n tr a c tile p e r f o r m a n c e a n d n o a r r h y th m ia , s id e b y s id e w ith o th e r o c c a s io n a l c h a g a s ic p a tie n ts w h o p r e s e n t s e v e r e d is o r d e r s o f r h y th m a n d /o r h e a r t f a ilu r e , w ith p r e s e r v a tio n o f a p r a c tic a lly n o r m a l p a tte r n o f a u to n o m ic r e s p o n s e to p h a r m a c o lo g ic a l a n d p h y s io lo g ic a l te s ts ( 4 9 ,6 2 ) ; e ) a ls o , f r o m a n a n a to m ic a l v ie w p o in t, th e a b s e n c e o f a c o r r e la tio n b e tw e e n d e n e r v a tio n a n d c lin ic a l c o u r s e , ty p e o f d e a th a n d p a th o lo g ic a l c h a r a c te r is tic s o f th e c h a g a s ic h e a r t h a s b e e n e m p h a s iz e d ( 4 0 ,4 1 ) ; f ) e v e n if th e p h y s io lo g ic a l a n d p h a r m a c o lo g ic a l p r in c ip le s o f th e c la s s ic a l d i v is io n o f th e a u to n o m ic s y s te m in to s y m p a th e tic a n d p a r a s y m p a th e tic c o m p o n e n ts c o n tin u e to b e c o n c e p tu a lly m a in ta in e d , m o d e r n s tu d ie s h a v e p o in te d o u t th e d if f ic u lty in d is tin g u is h in g th e m in a n a to m ic a l a n d f u n c tio n a l te r m s a t th e in tim a te le v e l in th e in n e r v a te d o r g a n ( 7 1 ) .
D e s p ite th e s e c r itic is m s o f th e n e u r o g e n ic th e o r y o f c h a g a s ic h e a r t d is e a s e , w h ic h w a s s u p p o r te d b y q u ite c o m p e llin g e x p e r im e n ta l r e s u lts ( 5 6 ) , it is p la u s ib le to a d m it th a t, a s a c o n tr ib u tin g m e c h a n is m , a u to n o m ic d e n e r v a tio n m a y r e p r e s e n t a r e le v a n t, if n o t p r im a r y o r e x c lu s iv e , f a c to r in th e p a th o g e n e s is o f th is c a r d io p a th y , c o n f e r r in g o n it p e c u lia r c h a r a c te r is tic s w h e n c o m p a r e d to th e o th e r a f f e c tio n s o f c a r d ia c m u s c le .
O n e s h o u ld a ls o r e c o g n iz e th e lim ita tio n s o f th e m e th o d s e m p lo y e d in a n a to m o p a th o lo g ic a l a n d p h y s io lo g ic a l s tu d ie s c a r r ie d o u t to d e te r m in e p o s s ib le a u to n o m ic a lte r a tio n s a t th e v e n tr ic u la r le v e l in c h a g a s ic h e a r ts . F o r e x a m p le , th e r e a r e n o s tu d ie s c o m p a r a b le to th o s e a b o u t th e p a th o lo g ic a l in v o lv e m e n t o f a tr ia l in n e r v a tio n a n d o f th e c o n d u c tio n s y s te m in th is s tr u c tu r e . S im ila r ly , w ith r a r e e x c e p tio n s ( s tu d y o f a tr io v e n tr ic u la r c o n d u c tio n [ 2 2 ] ) , th e p h y s io lo g ic a l s tu d ie s h a v e b e e n lim ite d to th e e f f e c ts o f d e n e r v a tio n o n th e s in u s n o d e . H o w e v e r , th e lite r a tu r e r e c o g n iz e s th e im p o r ta n c e o f v e n tr ic u la r p e r f o r m a n c e in f u n c tio n a l m o d u la tio n ( 6 9 ) .
FC DC V S P A M R V S
( b p m ) ( L / m in . ) ( m l) ( m m H o ) ( d . le c : . c m - S )
p < 0 . 0 1 NS p < 0 . 0 5 NS p < 0 . 0 5
110 7.0 80 100 1700
I
\
.---_.
100 6.0 70 90 1600
----.
90 5.0 60 80 1500
80 4.0 50 70 1400
I
.
I ITILT TILT TILT TILT TILT
Figure
8 . H e m o d y n a m ic a lte r a tio n s fo llo w in g p a s s iv e c h a n g e s in b o d y p o s itio n : n o r m a l c o n tr o ls ( s o lid lin e s a n d c ir c le s ) a n d c h a g a s ic p a tie n ts ( d a s h e d lin e s a n d tr ia n g le s ) . In th e c h a g a s ic g r o u p th e a b n o r m a l c h r o n o tr o p ic r e s p o n s e ( F C ) a p p e a r s to h a v e n o e ffe c ts o n c a r d ia c o u tp u t ( D C ) a n d s y s te m ic a r te r ia l p r e s s u r e ( P A M ) a s c o m p a r e d to n o r m a l s u b je c ts . H o w e v e r , p a tie n ts h a v e g r e a te r d e c r e a s e in s tr o k e v o lu m e ( V S ) a s s o c ia te d to h ig h e r in c r e a s e in s y s te m ic v a s c u la r r e s is ta n c e ( R V S ) .O n the other
hand,
there
is a lack of evolutionary
studies
correlating
anatom ical,
m yocardial
and rhythm ic
function
in chagasic
patients.
W ork on this subject
has
been underw ay
in our laboratory
for the past ten years,
and m ay
possibly
contribute
to the elucidation
of the
controversial
aspects
discussed
above.
Indeed,
it w ould
be illogical
to conclude
that an involvem ent
as m arked as
that of the neurovegetative
system
in Chagas'
disease
is
pathogenetically
irrelevant.
Its true
prevalence
in the
general chagasic
population
is unknow n,
but approxim ate
estim ates of 20 to 25% m ay be deduced for the m ost intense
degrees
of denervation
in unselected
sam ples
studied
in
Ribeirao
Preto
(47,52).
A nother
essential
characteristic
derived
from
recent
functional
studies
is
that
parasym pathetic
dysfunction,
although
varying
individually
from m inim al
degrees
to absolute degrees of
depression,
can
be
detected
by
increasingly
m ore
sophisticated
m ethods
in groups
representing
all clinical
form s-indeterm inate',
digestive,
cardiopathic
- of the
disease
(28,68).
A t
least
w hen
there
is an advanced
degree
of
denervation,
the chagasic
heart is deprived
of one of the
m ost relevant
m echanism s
of the so-called
cardiovascular
reserve
of hom eom etric
self-regulation
(66). The rapid
increase
in heart
rate is a com ponent
of the circulatory
adaptation to the w ide variety of situations
in w hich venous
return,
the
system ic
m etabolic
flow
dem and
or the
ventricular
afterload
are acutely
altered.
U nder
these
conditions,
the denervated
chagasic
heart start to depend
predom inantly
on heterom etric
adjustm ents,
w ith
the
occurrence
of m ore
conspicuous
variations
in cardiac
volum e
than those
detected
in norm al
individuals
from
the view point
of autonom ic
control.
Indeed,
it has been
clearly
show n
that
the
pattern
of the
hem odynam ic
response
to physical
effort can deviate
from norm ality
in
chagasic patients even w hen resting values are fully norm al
(26). In som e of these patients, the quotient of the variation
in cardiac
output to the increase
in oxygen
consum ption
im posed by effort w as found to be below the low er norm al
lim it, reflecting
an inadequate
response
to physical
effort.
H ow ever, perhaps m ore significantly,
instead of increasing
at the expense of increased only by the ejection
of a greater
volum e
per systole
(26). It m ay be proposed
that these
patients suffer a strong chronic
stim ulus
for the use of the
reserve m echanism
represented
by heart dilatation to satisfy
the habitual
increases
in blood
flow dem ands.
This m ay
represent
a deleterious
effect on the circulatory
dynam ics
of
chagasic
individuals
prim arily
due
to
cardiac
denervation.
C h a g a s i c p a t i e n t s a l s o s e e m t o h a v e p e c u l i a r f u n c t i o n a l c h a r a c t e r i s t i c s w i t h r e s p e c t t o t h e r e g u l a t i o n o f s y s t e m i c a r t e r i a l p r e s s u r e . T h e a t t e n u a t i o n o f t h e h y p e r t e n s i v e r e s p o n s e i n t h e p h a s e o f t h o r a c i c d e c o m p r e s s i o n o f t h e V a l s a l v a m a n e u v e r i s t y p i c a l l y s l o w e r t h a n i n n o r m a l i n d i v i d u a l s ( 4 4 ) . F u r t h e r m o r e , d u r i n g i s o m e t r i c e x e r c i s e , d e n e r v a t e d c h a g a s i c p a t i e n t s m a i n t a i n a h y p e r t e n s i v e p a t t e r n c o m p a r a b l e t o t h a t o f n o r m a l s u b j e c t s . H o w e v e r , w h e r e a s a t a c h y c a r d i a -d e p e n -d e n t i n c r e a s e d f l o w o c c u r s i n t h o s e c o n t r o l s , i n c h a g a s i c p a t i e n t s , w h o c a n n o t r e s p o n d t o t h e e f f o r t s t i m u l u s w i t h t a c h y c a r d i a , t h e i n c r e a s e i n s y s t e m i c a r t e r i a l p r e s s u r e i s e s s e n t i a l l y d u e t o t h e e l e v a t i o n i n p e r i p h e r a l v a s c u l a r r e s i s t a n c e ( 4 8 ) . O n e m a y s p e c u l a t e t h a t t h i s h e m o d y n a m i c b e h a v i o r i m p l i e s t h e p r e s e n c e o f a f r e q u e n t i n c r e a s e i n c i r c u l a t o r y a f t e r l o a d f o r v e n t r i c u l a r e j e c t i o n d u r i n g r o u t i n e d a i l y a c t i v i t i e s . T h e o r e t i c a l l y , t h i s m a y r e p r e s e n t a c o n s t a n t f a c t o r o f c h r o n i c s t r e s s i m p o s e d o n v e n t r i c u l a r p e r f o r m a n c e , w h i c h p o s s i b l y c o n t r i b u t e s t o t h e i n s t a l l a t i o n a n d / o r a g g r a v a t i o n o f t h e m y o c a r d i a l l e s i o n s i n t r i n s i c a l l y d u e t o t h e a g g r e s s i o n i m p o s e d o n t h e h e a r t b y t h e d i r e c t a n d / o r i n d i r e c t a c t i o n o f
T. cruzi.
C h a g a s i c p a t i e n t s w i t h c a r d i a c d y s a u t o n o m y a l s o c o m p e n s a t e f o r t h e i r d e f i c i e n t c h r o n o t r o p i c r e s p o n s e t o p o s t u r a l v a r i a t i o n s w i t h r e s p o n s e s o f s y s t e m i c v a s c u l a r r e s i s t a n c e s h a r p l y d i f f e r i n g f r o m t h o s e d e t e c t e d i n n o r m a l i n d i v i d u a l s ( 4 5 ) ( F i g . 8 ) .I f t h e s e a r e c o n c e i v a b l e p h y s i o p a t h o l o g i c a l p o s s i b i l i t i e s i n t e r m s o f c i r c u l a t o r y d y n a m i c s , i t i s i n t e r e s t i n g t o p r o p o s e t h a t a u t o n o m i c d y s f u n c t i o n w i l l p r o b a b l y c o n t r i b u t e t o t h e t y p i c a l d i s o r d e r s o f g e n e r a t i o n a n d c o n d u c t i o n o f e l e c t r i c s t i m u l i d e t e c t e d i n c h r o n i c C h a g a s ' h e a r t d i s e a s e ( 9 ) . F u r t h e r m o r e , a l t h o u g h a p r e l i m i n a r y s t u d y d i d n o t d e m o n s t r a t e a c o r r e l a t i o n b e t w e e n s i n u s d y s a u t o n o m y a n d v e n t r i c u l a r d y s r h y t h m i a ( 6 2 ) , o n e m a y p r o p o s e t h a t , a s i s t h e c a s e f o r t h e a u t o n o m i c d i s e q u i l i b r i u m a n d t r i g g e r i n g o f v e n t r i c u l a r f i b r i l l a t i o n o b s e r v e d a t t i m e s i n t h e a c u t e p h a s e o f n o t v e r y e x t e n s i v e m y o c a r d i a l i n f a r c t i o n s , t h e s u d d e n d e a t h o b s e r v e d i n c h a g a s i c p a t i e n t s i s v e r y p o s s i b l y d u e t o m e c h a n i s m s d e p e n d i n g o n d y s a u t o n o m y ( 5 8 ) . T h i s i n t e r p r e t a t i o n i s c o h e r e n t w i t h t h e r e p o r t s o f s m a l l , h i g h l y d e n e r v a t e d h e a r t s b y p a t h o l o g i s t s w h o p e r f o r m a u t o p s i e s o n c h a g a s i c s w h o d i e d s u d d e n l y ( 9 ,6 8 ) . W e s h o u l d a l s o p o i n t o u t t h e p o s s i b l e e f f e c t o f a l t e r e d p a r a s y m p a t h e t i c c o n t r o l o f t h e c o r o n a r y m i c r o c i r c u l a t i o n , w i t h r e p e r c u s s i o n s o n r e g i o n a l f l o w a n d m y o c a r d i a l m e t a b o l i s m ( 5 0 ) .
CHAGAS' DISEASE AS AN INTRINSIC
MODEL OF AUTONOMIC
DENERVATION
T h e o c c u r r e n c e o f e x t e n s i v e l y d e n e r v a t e d h u m a n h e a r t s w i t h p r a c t i c a l l y n o r m a l v e n t r i c u l a r p e r f o r m a n c e a n d t h e c o n s e q u e n t a b s e n c e o f t h e n o n s p e c i f i c e f f e c t s o f c a r d i a c f a i l u r e ( 2 9 ,5 1 ) p r o v i d e s a u n i q u e o p p o r t u n i t y f o r p h y s i o l o g i c a l s t u d i e s o f t h e c a r d i o v a s c u l a r s y s t e m ( 6 ) . H o w e v e r , t h e f o l l o w i n g l i m i t a t i o n s e x i s t a b o u t t h e u s e o f d e n e r v a t i o n o f c h a g a s i c e t i o l o g y a s a s p o n t a n e o u s e x p e r i m e n t a l m o d e l : a ) t h e d y s f u n c t i o n i s n o t r e s t r i c t e d t o o n e o f t h e a u t o n o m i c d i v i s i o n s ; b ) d e n e r v a t i o n d o e s n o t i n v o l v e a l l p a t i e n t s a n d t h e r e i s a n u n d e n i a b l e g e o g r a p h i c i n f l u e n c e ; c ) t h e i n d i v i d u a l d e g r e e o f d e n e r v a t i o n i s v a r i a b l e ; d ) s e v e r a l a n a t o m i c a l s i t e s o f t h e a u t o n o m i c s y s t e m a r e p a r t i a l l y a f f e c t e d a t t h e a f f e r e n t a n d c e n t r a l l e v e l s , a n d o b v i o u s l y m a i n l y a t t h e e f f e r e n t l e v e l .
W i t h r e s p e c t t o t h e s e r e s t r i c t i o n s , w e s h o u l d m e n t i o n t h e o b s e r v a t i o n o f e n z y m a t i c d i v e r s i t y a m o n g
T. cruzi
s t r a i n s s u g g e s t i n g t h a t v a r i a t i o n o f t h e e t i o l o g i c a l a g e n t m a y e x p l a i n t h e d i f f e r e n t c l i n i c a l m a n i f e s t a t i o n s ( 5 2 ) . I t s h o u l d a l s o b e p o i n t e d o u t t h a t e f f o r t s h a v e b e e n m a d e t o c h a r a c t e r i z e t h e d i f f e r e n c e s a m o n gTrypanosomatidae
s p e c i e s u s i n g m o l e c u l a r b i o l o g y m e t h o d s a n d p h y l o g e n e t i c a n a l y s i s ( 3 ,2 0 ,3 0 ) .
W i t h i n t h e a b o v e l i m i t a t i o n s , t h e s t u d y o f p a t i e n t s w i t h C h a g a s ' h e a r t d i s e a s e s e l e c t e d b y p r e s e n t i n g a n i n t e n s e d e g r e e o f d e n e r v a t i o n h a s p e r m i t t e d t h e u n d e r s t a n d i n g o f r e l e v a n t a s p e c t s o f c a r d i o v a s c u l a r p h y s i o l o g y . T o i l l u s t r a t e , w e s h a l l m e n t i o n t h e o r i g i n a l r e p o r t i n t h e i n t e r n a t i o n a l l i t e r a t u r e t h a t t a c h y c a r d i a e v o k e d i n h u m a n s b y t h e s t a n d i n g p o s i t i o n h a s a b i p h a s i c m e c h a n i s m ( 4 6 ) . A t f i r s t t h e r e i s a r e d u c t i o n o f v a g a l t o n u s n o t d e m o n s t r a b l e i n c h a g a s i c p a t i e n t s , a n d p r e d o m i n a n t l y a d r e n e r g i c s t i m u l a t i o n o c c u r s l a t e r . T h e s e e x p e r i m e n t a l r e s u l t s i l l u s t r a t e t h e c o n t r i b u t i o n o f t h e c h a g a s i c m o d e l t o r e s e a r c h i n t h e a r e a o f p h y s i o l o g i c a l c i r c u l a t i o n .
A p p l i c a t i o n o f s i m p l e , n o n i n v a s i v e a u t o n o m i c t e s t s w i t h n o r i s k f o r c h a g a s i c p a t i e n t s i n d i f f e r e n t g e o g r a p h i c r e g i o n s m a y n o t o n l y c l a r i f y t h e c o n t r o v e r s i a l .p h y s i o p a t h o l o g i c a l a s p e c t s d i s c u s s e d a b o v e , b u t a l s o
p e r m i t n e w a d v a n c e s i n t h e u n d e r s t a n d i n g o f c a r d i o v a s c u l a r f u n c t i o n a l i t y i t s e l f . F i n a l l y , i t w i l l b e n e c e s s a r y t o r e e v a l u a t e i n h u m a n s t u d i e s t h e p o s s i b i l i t y d e l i n e a t e d i n e x p e r i m e n t a l s t u d i e s o f t h e r e v e r s i b i l i t y o f n e r v o u s l e s i o n s d e t e c t e d i n t h e a c u t e p h a s e o f
T. cruzi
i n f e c t i o n ( 4 3 ) .
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