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Neuroscience &Biobehavioral Reviews,Vol. 7, pp. 511-527, 1983. Ankho International nc. Printed n the U.S.A.

Stress , Predisposi t ion and the Onset ofSerious Disease: Impl icat ions About

Psychosomat ic Et io logyB E N J A M I N H . N A T E L S O N

Primate Neuro-Behavioral Unit, VA Medical Center and Department of NeurosciencesUniversity of Medicine and Dentistry-New Jersey Medical School, East Orange, NJ 07019

NATELSON, B. H. Stress, predisposition and the onset of serious disease: Implications about psychosomatic etiology.NEUROSCI BIOBEHAV REV 7(4) 511-527, 1983.--Based on the author's own work and a review of the literature, thehypothesis is made that potentially lethal disease does not usually occur in healthy animals or people but does so whencovert or overt disease exists or when a predisposition for disease exists. The author supports this hypothesis in hisassessment of the human literature on sudden death. Further support for the hypothesis is presented from 2 animal modelsbeing studied in his laboratory--stress-induced heart failure in the cardiomyopathic hamster and stress-induced sensitiza-tion of digitalis-toxic ventricular arrhythmias. This analysis suggests a different view from the classical one of what apsychosomatic disease might be.Stress Sudden death Cardiac arrhythmias Peptic ulcer disease Psychosomatic diseaseMyocardial infarction Cardiomyopathy

FIRS T Bea umon t [8], later Can non [18], and then Selye [113]made the important point that emotional arousal or stresscould produce profound changes in activity of a whole hostof visceral systems. Indeed these are commonly reflected inour everyday discourse with statements such as: "Thatmakes me sick to my stomach (makes my heart pound,etc.)." However, whether or not these changes in visceralactivity ever result in frank, serious organic disease is farless clear. The notion that stress can produce such an out-come is a major tenet of the psychosomatic concept. And,psychosomatic factors are commonl y invoked when discuss-ing the pathogenesis of poorly understood diseases such aspeptic ulcers. Howe ver, a review of what has been written toassess the importance of psychosomatic factors in thegenesis of diseases such as peptic ulcers leaves one uncon-vinced [35].

IMPORTANCE OF THE "EXECUTIVE" MONKEY EXPERIMENTBecause of this, the "e xecut ive" monkey experiment wasa bellwether for students interested in psychosomatic dis-ease. In this work, a group from the Walter Reed ArmyInstitut e of Research [14] reported that mo nkeys working toavoid shock--but not their yoked controls which could notaffect shock delivery--became sick over the course of amonth and died; pathological examination revealed frankpeptic ulcer disease in all these monkeys. To comprehendthe reason for the excitem ent which greeted the report of this

experiment, one must rem ember that the major animal modelfor stress-induced gastric disease had been developed in therat. But, stressed rats rarely developed severe gastric lesionsthat extended beyond the muscularis mucosae of thestomach wall [67]; thus, although called "stress ulcers,"these lesions were n ot really ulcers, since they did not meetthe ope rational definition of this lesion [15]. In con trast, thedisease that was found in the "executive" monkeys wasserious [14]. Lesions extended beyond the muscularismucosae and thus fulfilled the operational definition of ul-cers. Of equal importance was the location of the diseasethat was found in the stressed monkeys. It developed in thesame part of the gastrointestinal tract in which peptic ulcersdevelop in man, namely distal stomach and duodenum [94].In contrast, the disease that develops in the stressed rat doesso in proximal stomach where the acid-secreting cells arelocated [67]. Thus, the excit ement concern ing the "e xecu-tive" monkey experiment occurred for a number of reasons.First, because it promised an animal model that seemed toclosely emulate the human condition. And second, becauseit did so by manipulating the animal's environm ent ratherthan by ma nipulating its stomach or the nerves to itsstomach; thus, the disease was psychosomatic in origin.The problem with this model was that it was difficult toreplicate. In the hands of a n umb er of groups including theoriginal one from Walter Reed, monkeys put in the sameparadigm never died. And, when they were sacrificed afterbeing on the avoidance schedule for one month, their GI

~The work from this laboratory reviewed in this paper was supported by VA medical research funds, by grant No. HL-24498 from theNational Heart, Lung and Blood Institute and by grants from the American Heart Association, New Jersey Affiliate.

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FIG . I . M ean p l a sm a co r t iso l f o r a g roup o f mo n k e y s d u r i ng basa lcond i t i ons and du r ing t he f i r s t and e l even th 6 h r s e s s ion o f f r ee -ope ran t a vo idance ( f rom [92 ] ) . N o te t he rob us t co r t i so l r e sponsedur ing t he f i r s t such sess ion . B y the e l even th s e s s ion , t he r e sponsehas habi tuated . Thi s i s not mere ly du e to the monk eys ' l e a rn ing t heavo idance t a sk because l eve l s r em a in suppre s sed even a f t e r un -avo idab l e shock i s supe r im posed .

t r a c t w a s f o u n d e i t h e r t o b e f r ee o f d i s e a s e o r to h a v e r a t h e rt r i v i a l d i s e a s e ( f o r d e t a i l s s e e [ 8 4] ). I n t h i n k i n g a b o u t t h i sp r o b l e m , I h y p o t h e s i z e d t h a t p e r h a p s m o n k e y s h a d d e v e l -o p e d f r a n k p e p t i c u l c e rs b u t t h a t s o m e h o w t h e y h a dh a b i t u a t e d t o t h e s t r e s s o f th e a v o i d a n c e t a s k , a n d t h u s , t h eu l c e r s h a d h e a l e d . I b a s e d t h i s n o t i o n o n d a t a c o l l e c t e d fr o mm o n k e y s p e r f o r m i n g f r e e - o p e r a n t a v o i d a n c e d u r i n g d a i l y 6h r s e s s i o n s [ 9 2 ] . F i g u r e 1 s h o w s t h e e x p e r im e n t . D u r i n g t h ef i rs t a v o i d a n c e s e s s i o n , t h e g r o u p o f c h r o n i c a l l y c a th e -t e r i z e d , c h a i r - a d a p t e d m o n k e y s s h o w e d a r o b u s t c o r t i s o l r e -s p o n s e w h e n c o m p a r e d t o le v e l s c o l l e c t e d o n a c o n t r o l d a y i nw h i c h t h e m o n k e y s w e r e n o t d is t u r b e d . H o w e v e r , b y t h ee l e v e n t h s u c h s e s s i o n , t h e c o r t i s o l r e s p o n s e h a d d i s a p p e a r e da n d l e v e l s w e r e i n f a c t e v e n l o w e r t h a n o n t h e c o n t r o l d a y .T h i s w a s n o t m e r e l y d u e t o t h e fa c t t h a t t h e m o n k e y s h a dl e a r n e d h o w t o a v o i d s h o c k b e c a u s e c o r t i s o l l e v e l s w e r e s t i l ll o w e v e n a f t e r th e s u p e r i m p o s i t i o n o f u n a v o i d a b l e s h o c kw h i c h p r o d u c e d a s t r i k in g i n c r e a s e i n th e m o n k e y s 'a v o i d a n c e r e s p o n s e r a t e .

MULTIPLE STRESS AND G ASTRO-DUODENALDISEASEIN MONKEYSI d e c i d e d t o u s e a n e x p e r i m e n t a l d e s i g n w h i c h m i n i m i z e dt h e p o s s i b i l i t y o f t h is s o r t o f m a r k e d h a b i t u a t i o n o f v i s c e r a la c t i v a t i o n f r o m o c c u r r i n g . T h e g o a l o f t h e e x p e r i m e n t w a s t op r o d u c e u n e q u i v o c a l s e v e r e p e p t i c u l c e r d i s e a s e i n m o n -k e y s . M y p l a n w a s t o d e v e l o p a m u l t i p l e s t r e s sw h i c h c o u l d b e c h a n g e d w h e n e v e r a d e q u a t e ~ b e h a v i o rw a s s e e n . T o d o t h i s, I t u r n e d t o W e i s s ' w o r k w h i c h h a s b e e ns e m i n a l i n e l u c i d a t i n g t h e p s y c h o l o g i c a l p r i n c i p l e s r e s p o n s i -b le f o r t h e i n i t i a t io n o f t h e r e l a t i v e l y m i l d ~ d i s e a s e t h a to c c u r s i n s t r e s s e d r a t s [ 1 2 8 ] . T h e s e v a r i a b l e s , r a n k e d int e r m s o f th e i r p a t h o g e n e t i c e f f e c t , i n c l u d e d u n p r e d i c t a b i l i t yo f t i m e o f d e f i v e r y o f n o c i c e p t i v e s t i m u l i , i n a b i li t y t o c o n t r o ls u c h s t i m u l i, a n d p u n i s h m e n t o f p r e v i o u s l y a p p r o p r i a te r e-s p o n s e s ( i . e . , c o n f l i c t ) . T h u s , m y e x p e r i m e n t a l d e s i g n w a s t o

d e l i v e r sh o c k t r a i n s u n p r e d i c t a b l y a t a t im e w h e n m o n k e y s

w e r e j u s t l e a r n i n g h o w t o e s c a p e s u c h t r a in s . T h e n w h e na s y m p t o t i c e s c a p e b e h a v i o r w a s s e e n , th e m o n k e y s w e r es w i t c h e d o n t o a s h o c k a v o i d a n c e s c h e d u l e w h i c h w a s t h es a m e a s t h a t u s e d b y t h e o r i g i n a l g r o u p o f i n v e s t i g a t o r s .H e r e , t h e m o n k e y h a d t o p r e s s a l e v e r e v e r y 2 0 s e c to a v o i ds h o c k ; i f r e s p o n d i n g s t o p p e d , f o o t s h o c k w a s d e l i v e r e d o n c ea s e c u n ti l a n e s c a p e r e s p o n s e w a s m a d e . A g a i n w h e n s t a b lep e r f o r m a n c e w a s d i s p l a y e d , th e t a s k w a s a g a i n c h a n g e d t oo n e i n w h i c h p r e v i o u s l y a p p r o p r i a t e e s c a p e r e s p o n s e s w e r ep u n i s h e d w i t h a s li g h t l y h i g h e r i n t e n s i t y s h o c k . F i n a l l y ,w h e n a s y m p t o t i c b e h a v i o r w a s a g a i n s e e n , th e t a s k w a sa g a i n c h a n g e d s o t h a t p r e v i o u s l y a p p r o p r i a t e a v o i d a n c e re-.s p o n s e s w e r e n o w o c c a s i o n a l l y p u n i s h e d b y a l e s s i n t e n s es h o c k . T h e o t h e r s t r a t e g y I c h o s e t o e v a l u a t e m y i d e a t h a td i s e a s e d i d d e v e l o p b u t h e a l e d a s t h e a n i m a l h a b i t u a t e d t o i tss t r e s s f u l d e m a n d s w a s t o p l a n t o d i r e c t l y v i s u a l iz e t h e d i s t a lh a l f o f t h e s t o m a c h ( i . e . , c o r p u s a n d a n t r u m ) a n d t h e f i r s t f e wi n c h e s o f t h e d u o d e n u m u s i n g a f l e x i b l e f i b e r o p t i ce n d o s c o p e ; t h u s , m o n k e y s w e r e r e m o v e d f r o m t h e ir c h a i r sa n d p l a c e d i n t h e l e ft l a te r a l d e c u b i t u s p o s i t i o n t w i c e w e e k l y ,a n d e n d o s c o p y w a s p e r f o r m e d i n i ti a ll y t h r o u g h a g a s t r o t o m ya n d l a t e r t h r o u g h a n e s o p h a g o s t o m y .T h e r e s u l t s [ 8 4 ,9 0 ] w e r e t h a t d i s e a s e w a s f o u n d i n 3 (F /~ o ft h e e x a m i n a t i o n s . I m p o r t a n t l y , t h e d i s e a s e d e v e l o p e d i n th es a m e p a r t o f th e g u t i n w h i c h h u m a n d i s e a s e i s s e e n [ 9 4] . F o rt h e m o s t p a r t , l e s io n s w e r e f o u n d a t t h e j u n c t i o n b e t w e e n t h ec o r p u s a n d t h e a n t r u m , i n t h e a n t r u m o r in t h e d u o d e n u m .U n f o r t u n a t e l y , t h e d i s e a s e t h a t d i d d e v e l o p w a s e v a n e s c e n t .T h a t i s , w h e n l e s i o n s w e r e f o u n d i n t h e s t o m a c h , t h e y u s u -a l l y d i s a p p e a r e d i n a f e w d a y s . T h e l e s io n s w e r e s o m e w h a tl e s s e p h e m e r a l w h e n f o u n d i n t h e d u o d e n u m , b u t e v e n t h e s ed i s a p p e a r e d i n a b o u t a w e e k . S e v e r a l o f t h e s e l e s io n s w e r ee x a m i n e d p a t h o l o g i c a l ly . S e v e r a l g a s t r ic l e s i o n s w e r e f o u n dt o b e e r o s i o n s ( i . e . , t h e y d i d n o t p e n e t r a t e t h e m u s c u l a r i sm u c o s a e ) . O n e d u o d e n a l le s i o n w a s e x a m i n e d a n d r e v e a l e db l u n t e d d u o d e n a l v i l l a e w i t h m u c o s a l s t a i n i n g c h a r a c t e r i s t i co f g a s t r i c m e t a p l a s i a ; i m p o r t a n t l y , t h i s l e s i o n h a s b e e n d e -s c r i b e d i n p a t i e n t s w i t h d u o d e n i t i s a n d i s f o u n d t o o c c u r n e a rp e p t i c u l c e r s [ 2 7 ].F i g u r e 2 s h o w s w h e n d i s e a s e d e v e l o p e d i n t h e c o u r s e o ft h e e x p e r i m e n t . D i s e a s e w a s n e v e r s e e n d u r i n g c o n t r o lp e r i o d s . I n t h e f i r s t 3 c o n d i t i o n s , e i t h e r 3 o r 4 m o n k e y se v i n c e d d i s e a s e . B u t , i n t h e l a s t p h a s e o f th e e x p e r i m e n tw h e n b e h a v i o r a p p e a r e d m o s t d i s r u p t e d d u e t o th e f a c t t h a tp r e v i o u s l y a p p r o p r i a t e r e s p o n s e s w e r e b e i n g p u n i s h e d , 7 o ft h e 8 m o n k e y s w e r e f o u n d t o h a v e d i s e a s e .T h u s , d e s p i t e t h e s t r a te g y c h o s e n , c h r o n i c p e p t i c u l c e rd i s e a s e d i d n o t d e v e l o p i n t hi s g r o u p o f c h r o n i c a l l y s t re s s e dm o n k e y s . H o w e v e r , l e s s s e v e r e d i s e a s e re l i a b ly d e v e l o p e d :i t o c c u r r e d i n t h e s a m e p a r t o f t h e p a r t o f t h e g u t a s d o e s t h ed i s e a s e t h a t o c c u r s i n m a n ; a n d . i t s p r e s e n c e r e l a t e d to t h ec o n t i n g e n c i e s i m p o s e d o n t h e m o n k e y s , a n d i t w a s t h e r e f o r ep s y c h o s o m a t i c .T h e f a c t t h a t s e r i o u s d i s e a s e d i d n o t d e v e l o p i n t h e s em o n k e y s m a d e m e b e g i n to q u e s t i o n t h e b a s i s o f t h ep s y c h o s o m a t i c h y p o t h e s i s . B a s e d o n m y o w n d a t a . I w o n -d e r e d w h e t h e r s e r i o u s ( i . e . , p o t e n t i a l l y l e t h a l ) d i s e a s e e v e rd e v e l o p e d w h e n h e a l t h y a n i m a l s w e r e s u b j e c t e d t o s t r e ss .

EFFECT OF STRESS ON VITAL PROCESSES IN H EALTH AN IMALSI n f a c t , a li t e r a t u r e r e v i e w r e v e a l s o n l y a f e w s t u d i e ss h o w i n g t h a t s t r e s s i n n o r m a l a n i m a l s c a n h a v e l e th a l c o n s e -q u e n c e s . T h e s e s t u d i e s h o l d i n c o m m o n t h e f a c t t h a t a v a r i-

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FIG . 2 . Pe rcen t o f ga s t ro -duodena l exam ina t ions w h ich w ere ab -norm al ( from [90]) . Dots p lot ted abo ve eac h l ink in the mu l t ip les t r e s s pa r ad igm r ep re sen t i nd iv idua l m on keys ' da t a . N o te t ha t ab -no rm a l exam s w ere nev e r found du r ing con t ro l pe r i ods ; du r ing t hef i r s t 3 expe r im en ta l com ponen t s , 3 o r 4 o f t he m onkeys dev e lopedl e s ions ; du r ing the l a s t com ponen t w hen t he m os t exc i t ed behav io rw as d i sp l ayed com m ensura t e w i th t he con f l i c t ta sk im posed , 7 o f t he8 m onkey s w ere no t ed t o have l e s ions .

p r o d u c e d e a t h . T h e b e s t o f t h e s e i s th a t o f v o n H o i s t [ 12 6 ].H e s h o w e d t h a t r e p e a t e d b r i e f c o n f r o n t a t i o n s b e t w e e n a na g g r e s s i v e d o m i n a n t t r e e s h r e w a n d a s u b j u g a t e d i n f e r i o rp r o d u c e d a l e t h a l o u t c o m e d u e t o r e n a l f a i lu r e in th e l a t t e ra n i m a l i n 2 t o 1 0 d a y s . S i m i l a r l y , H e n r y e t a l . [ 5 1 ] s h o w e dt h a t m i c e , i s o l a t e d f o r 4 m o n t h s a f t e r w e a n i n g , d e v e l o p e ds y s t o l i c h y p e r t e n s i o n w h e n p u t i n t o a s o c i a l s i t u a t i o n inw h i c h c o n t a c t w i t h o t h e r m i c e w a s m a n d a t o r y . A f t e r a t l e a s t5 m o n t h s h a d p a s s e d , s o m e m i c e d i e d a n d a u t o p s i e s r e v e a l e dr e n a l a n d c a r d i a c p a t h o l o g y [ 50 ] ; w h e n m i c e w e r e s a c r i f i c e de a r l i e r t h a n 5 m o n t h s , d i s e a s e w a s n o t f o u n d [ 29 ] . E f f o r t s tot a k e t h i s m o d e l t o r a t s w e r e l e s s s u c c e s s f u l a s o n l y 1/3 o f th er a t s d e v e l o p e d a n y i n c r e a s e i n b l o o d p r e s s u r e a n d e v e n i nt h e s e a n i m a l s , t h e p r e s s u r e c h a n g e w a s n o t l a r g e [ 3 ] . W h e na d d i t i o n a l p h y s i c a l s t re s s o r s a r e i m p o s e d s u c h a s c r o w d i n g ,f l a s h i n g l i g h t s , l o u d n o i s e a n d c a g e o s c i l l a t i o n , r a t s d e v e l o pf r a n k h y p e r t e n s i o n b y t h e t h i rd m o n t h a n d d e a t h s o c c a s i o n -a l ly o c c u r [ 5 5 ]. T h e h y p e r t e n s i o n r e m a i n s e v e n a f t e r t h ep h y s i c a l s t r e s s i s s t o p p e d [ 9 6 ] .S e p a r a t i o n b e t w e e n p h y s i c a l a n d p s y c h o l o g i c a l f ac t o r s i nt h e p a t h o g e n e s i s o f d i s e a s e i s l e s s c l e a r in t h e l a t t e r e x p e r i -m e n t s t h a n i n t h o s e o f v o n H o i s t . I n h i s w o r k [ 1 2 6 ], t r e es h r e w s a r e a l l o w e d o n l y m i n i m a l p h y s i c a l c o n t a c t w i t h o n ea n o t h e r , w h e r e a s t h e m i c e o f H e n r y e t a l . a r e f r e q u e n t l yf i g h t i n g - - s o m u c h s o , i n f a c t , t h a t it b e c a m e i m p o s s i b l e toi n d i r e c tl y m e a s u r e b l o o d p r e s s u r e i n t h e t r a u m a t i z e d t a i ls o ft h e m i c e [ 5 1] . A l t h o u g h i t i s c l e a r f r o m t h e s e s t u d i e s t h a ts o c i a l f a c t o r s c a n p r o d u c e d i s e a s e a n d d e a t h , i t i s n o t c l e a r

w h e t h e r t h e p s y c h o s o m a t i c e f f e c t i s d u e t o t h e p h y s i c a ls t r e s s o f f ig h t in g w i t h i ts c o n c o m i t a n t w o u n d s o r t o s o m ep s y c h o l o g i c a l f a c to r i n h e r e n t t o t h e e x p e r i m e n t a l p a r a d i g m .A n a d d i t i o n a l p o i n t t o c o n s i d e r i s t h a t t h e d i e t s o f t h e s e m i c ec o n t a i n e d 0 . 5 t o 1 % s o d i u m c h l o r i d e ; t h i s r e l a t i v e s o d i u ml o a d m i g h t h a v e a c t e d a s a p r e d i s p o s i n g a g e n t t o s e n s i t i z e th em i c e t o s t r e s s ( s e e b e l o w ) .

O t h e r e f f o rt s t o p r o d u c e l e th a l d i s e a s e i n n o r m a l a n i m a l sb y s o c i a l s t im u l i h a v e m e t w i th v a r y i n g s u c c e s s . W e b e r a n dv a n d e r W a l t [1 27 ] w e r e t h e m o s t s u c c e s s f u l . T h e y s u b j e c t e dr a b b i t s t o c r o w d i n g s t r e s s a l t e r n a t e d w i t h i s o l a t i o n . O f t h e 4 8r a b b i t s s t u d i e d o v e r t h e 10 m o n t h e x p e r i m e n t a l p e r i o d , 35d i e d . P a t h o l o g ic e x a m i n a t i o n r e v e a l e d c a r d i o m y o p a t h y - - t h ep r e s u m p t i v e c a u s e o f d e a t h . T h e b e h a v i o r o f t h e s e a n i m a l sw a s n o t s t u d i e d o v e r t h is e x p e r i m e n t a l p e r io d . I n o t h e rw o r k , R a t c l if f e [1 01 ] n o t e d t h a t t h e i n c i d e n c e o f c o r o n a r ya r t e r y d i s e a s e w i th m y o c a r d i a l i n fa r c t io n i n c r e a s e d s u b s t a n -t i a l ly in a z o o p o p u l a t i o n i n th e 1 96 0s . H e c o r r e l a t e d t h i si n c r e a s e d p r e v a l e n c e w i t h t h e z o o ' s a t t e m p t t o e s t a b l i sh a n dm a i n t a i n b r e e d i n g p a i rs a n d g r o u p s o f m a m m a l s a n d b i r d sw h i c h i n c r e a s e d s o c i a l i n t e r a c ti o n a m o n g t h e a n i m a l s . T ot e s t t h i s f u r t h e r , h e a l l o w e d c h i c k e n s t o l i v e s i n g l y a n d i nh e t e r o s e x u a l g r o u p s f o r n e a r l y a y e a r [ 1 0 2 ] a n d f o u n d t h a tm y o c a r d i a l d is e a s e d e v e l o p e d i n th e g r o u p e d c h i c k e n s . A l -t h o u g h t h i s s u g g e s t e d t o th e a u t h o r s t h a t s o c i a l s t r e s sp r o d u c e d h e a r t d i s e a s e , t h e i r e f f o r ts t o f in d s i m i l a r d a t a i ns w i n e w e r e u n s u c c e s s f u l [ 1 0 3 ] . I n f a c t , t h e y f o u n d t h e e x a c to p p o s i t e r e l a t io n : C o r o n a r y a r t e r i o s c l e r o s i s w a s m o s t a d -v a n c e d i n s i n g l y c a g e d s w i n e . B a n e r j e e [ 6] w a s e v e n l e s ss u c c e s s f u l . H e t r a i n e d o t h e r w i s e i s o l a t e d m i c e to f i g h t w h e nc o n f r o n t e d w i t h a n o t h e r m o u s e a n d r e p e a t e d l y a l l o w e d s u chb o u t s o f fi g ht in g o v e r m o n t h s . T h e i s o l a te s d e v e l o p e d d e n u -d a t i o n s o f b o d y h a i r a n d o c c a s i o n a l s k i n s o re s . H o w e v e r , t h et i m e o f d e a t h i n th e s e m i c e w a s n o t d i f f e r e n t f r o m c o n t r o l s ,a n d t h e n e p h r o s c l e r o t i c c h a n g e s f o u n d a t a u t o p s y w e r e s a i dt o b e c o m m o n i n m i c e o f a s i m i l a r a g e . T h i s r e p o r t e m p h a -s i z e s t h e n e e d f o r c a r e f u l c o n t r o l s i n a s s e s s i n g f r a n k p a t h o l -o g y . I n d e e d , i n H e n r y ' s e a r l y r e p o r t [ 51 ] , m a l e m i c e t h a tg r e w u p i n t h e s o c i a l s t r e s s s i t u a t i o n h a d m o d e r a t e l y e l e -v a t e d b l o o d p r e s s u r e s w h e n c o m p a r e d t o s in g l y c a g e d c o n -t r o is . T h i s c o u l d b e i n t e r p r e t a t e d t o m e a n t h a t b l o o d p r e s -s u r e s i n t h e 1 4 0 m m r a n g e a r e n o r m a l f o r m i c e i n s o c i a ls i t u a t i o n s a n d t h a t i s o l a t i o n i t s e l f r e d u c e s b l o o d p r e s s u r e sa n d m i g h t b e c o n s t r u e d a s a " t h e r a p e u t i c " i n t e r v e n ti o n .W h e n s q u i r r e l m o n k e y s [ 11 ] a n d r h e s u s m o n k e y s [ 3 6]w e r e r e q u i r e d t o p e r f o r m o p e r a n t t a s k s t o a v o i d s h o c k , f r a n kh y p e r t e n s i o n d e v e l o p e d a h a l f a y e a r l a te r . T h i s h y p e r t e n -s i o n w a s n o t c o n f i n e d t o t h e p e r i o d w h e n t h e o p e r a n ts c h e d u l e s w e r e i n e f f e c t . I n c o n t r a s t t o w h a t h a p p e n s i n t h es t r e s s e d r a t , t h e h y p e r t e n s i o n w a s n o t s u s t a i n e d in t h em o n k e y - - a l w a y s r e t u rn i n g to w a r d b a s e l i n e l e v e ls w h e n t h em o n k e y s n o l o n g e r h a d t o p e r f o r m t h e s h o c k a v o id a n ce "t a s k s . A l s o , p o s t m o r t e m e x a m i n a t i o n s d i d n o t r e v e a l a n yc o n s i s t e n t p a t h o l o g y . I n o t h e r e f f o r t s , F i n d l e y e t a l . [34]w e r e u n s u c c e s s f u l in p r o d u c i n g e l e v a t e d b l o o d p r e s s u r e i nb a b o o n s w o r k i n g t o a v o i d s h o c k i n s e s s i o n s l as t in g o v e r ay e a r .

I n c o n t r a s t t o t h e s e s t u d i e s i n w h i c h s t r e s s i s q u i t e l o n g ind u r a t i o n , a n u m b e r o f w o r k e r s h a v e s t u d i e d a n im a l m o d e l s i nw h i c h d e a t h o c c u r s s u d d e n l y f o l lo w i n g s o m e p e r t u r b a t i o n o ft h e e n v i r o n m e n t . R i c h t e r [ 1 06 ] w a s o n e o f t h e f ir s t t o s y s -t e m a t i c a l l y s t u d y th i s w h e n h e s u b j e c t e d w i l d r a t s t o s w i m -m i n g s t r e s s. H e n o t e d t h a t t h e s e a n i m a l s o f t e n d i v e d a n dt h e n d e v e l o p e d a p r o f o u n d b r a d y c a r d i a l e a d in g to a s y s t o l e .I f g i v e n p r i o r e x p e r i e n c e a t s w i m m i n g , t h i s l e t h a l e ff e c t w a s


4/17

514 N ~ V [ ' EL . S t )N

p r e v e n t e d . S i n c e t h e s e e a r ly e x p e r i m e n t s , t h i s m o d e l h a sb e e n e x t e n s i v e l y s t u d i e d ( s e e r e v i e w i n [5 6 ]) . A l t h o u g h t h i sm o d e l d o e s o c c u r i n n o r m a l r a t s , i t a p p e a r s t h a t t h e s w i m -m i n g p a r a d i g m i n t r o d u c e s a n e l e m e n t o f s e n s i t iz a t i o n d u e t oi ts e l ic i t a ti o n o f th e " d i v i n g r e f l e x , " a n o x y g e n c o n s e r v i n gr e f le x c h a r a c t e r i z e d b y m a r k e d b r a d y c a r d i a a n d o c c u r r i n g ina n y m a m m m a l f o l lo w i n g f a c e i m m e r s i o n [ 6 3, 13 0 ]. W h e n t h i sr e f le x i s b l o c k e d b y a t r o p i n i z a ti o n , t h e p r o b a b i l i t y o f s u d d e nd e a t h d e c r e a s e s [ 1 0 6 ] .T h e r e a r e h o w e v e r o t h e r s u d d e n d e a t h m o d e l s in a n im a l si n w h i c h t h i s t r i g e m i n o - m e s e n c e p h a l i c r e fl e x i s n o t s t i m u -l a t e d . T h e m o s t i n t e r e s t i n g o f t h e s e o c c u r s i n a n a g g r e s s i v eb o u t f o r d o m i n a n c e b e t w e e n 2 m a l e s t r e e s h r e w s [ 1 26 ]. F o l -l o w i n g a b r i e f b a t t l e , t h e d e f e a t e d s h r e w l i e s q u i e t l y b u ta l e r t l y . I f t h e d o m i n a n t a n i m a l i s n o t t h e n r e m o v e d , i t w i l lc o n t i n u e t o a t t a c k t h e d e f e a t e d s h r e w b u t w i l l d o l i t tl e p h y s i -c a l d a m a g e . S o o n t h e r e a f t e r , t h e d e f e a t e d a n i m a l w i l l b e g i nb r e a t h i n g i r r e g u l a r l y , t h e n s t o p b r e a t h i n g a n d d i e . A s i m i l a rs y n d r o m e h a s b e e n r e p o r t e d i n w i ld N o r w a y r a ts b u t n o t ina l b i n o r at s w h e n a n e w c o m e r m a l e is p l a c e d i n to a n e s t a b -l i s h e d c o l o n y [ 7 ]. S i m i l a r i n s t a n c e s o f s u d d e n d e a t h i n z o oa n i m a l s h a v e b e e n r e p o r t e d t o r a r e l y f o ll o w s i m i l a r s e e m -i n g l y m i l d e n v i r o n m e n t a l p e r t u r b a t i o n s [ 1 9 ].I n o t h e r s t u d i e s [ 6 0 ] , a l e r t p i g s w e r e r e n d e r e d i m m o b i l eb u t w i t h n o r m a l r e s p i r a t i o n b y a p a r a l y t i c a g e n t a n d t h e nw e r e s u b j e c t e d t o o c c a s i o n a l e l e c t r i c s h o c k t o t h e h i n d l e gf o r t h e n e x t 1 5 - 2 0 m i n . S e r i o u s a r r h y t h m i a s d e v e l o p e d in 1 6o f t h e 2 3 p ig s s t u d i e d b u t w e r e s e l f - l im i t e d f o r 1 3. W h e n t h ep i g s w e r e s a c r i f ic e d 2 d a y s l a t e r, m a c r o s c o p i c a n d m i c r o -s c o p i c p a t h o l o g i c a l c h a n g e s w e r e f o u n d i n th e h e a r t s o fn e a r l y e v e r y a n i m a l ; t h e s e w e r e n o t f o u n d i n c o n t r o l p i g s .B a s e d o n t h e s e d a t a a n d t h e f a c t t h a t s u d d e n d e a t h i s n o tu n u s u a l a m o n g p i g s h a n d l e d f o r s l a u g h t e r , t h e a u t h o r s c o n -c l u d e d t h a t t h e m y o c a r d i u m o f th e p i g is m o r e s u s c e p t i b l e tos t r e s s t h a n t h a t o f o t h e r s p e c i e s u s e d i n s t r e s s r e s e a r c h .

T h e f i n a l s e t o f e x p e r i m e n t s i n v o l v e s c h a i r e d s q u i r r e lm o n k e y s w h i c h w e r e r e p o r t e d t o d i e e i t h e r w h i le p e r f o r m i n gf r e e - o p e r a n t a v o i d a n c e o r w h i le r e c e i v i n g u n c o n t r o l l a b les h o c k . I n t h e f ir s t e x p e r i m e n t [ 2 5 ], 2 o f 9 a v o i d a n c e m o n k e y sd i e d ; n e c r o p s y o f s u rv i v i n g a v o i d a n c e m o n k e y s r e v e a l e dm y o c a r d i a l h i st o l o g i c a b n o r m a l i t i e s w h i c h , s u r p r i s i n g l y , i nv i e w o f th e s h o r t e x p e r i m e n t a l d u r a t io n ( u p t o l 0 d a y s w o r k -i n g a l t e r n a t e 8 h r a v o i d a n c e s e s s i o n s ) , i n c l u d e d f i b r o s i s . I n ar e p l i c a t i o n u s i n g y o k e d c o n t r o l s t h a t c o u l d n o t a f f e c t s h o c kd e l i v e r y [ 2 2] , C o r l e y e t a l . r e p o r t e d t h a t t h e y o k e d a n i m a l s ,n o t t h e a v o i d a n c e m o n k e y s , d e t e r i o r a t e d p h y s i c a l l y a n d t h e nd i e d a f t e r m a n i f e s t i n g v e r y s l o w h e a r t r a t e s o n e l e c t r o c a r -d i o g r a m . N e x t , C o d e y e t a l . [ 7 7 ] i n c r e a s e d s t r e s s b y d e -m a n d i n g t h e i r m o n k e y s p e r f o r m t h e a v o i d a n c e t a s k f o r 24 h rw i t h n o p r io r a v o i d a n c e t r a in i n g . T h r e e a v o i d a n c e m o n k e y sa n d o n e y o k e d m o n k e y d i e d o f b r a d y c a r d i a a n d c a rd i a cs t a n d s t i l l d u r i n g o r s o o n a f t e r t h e 2 4 h r s tr e s s . M i c r o s c o p i ce x a m i n a t i o n o f t h e g r o s s l y n o r m a l h e a r t s r e v e a l e d m y o f i b r il -l a r d e g e n e r a t i o n i n a ll a n i m a l s b u t m o r e s o i n a n i m a l s w o r k -i n g t o c o n t r o l s h o c k . T h e v a r i a b i l i t y o f r e s u l t s a c r o s s t h e s e 3e x p e r i m e n t s m a k e s a n a l y s i s d i f f ic u l t . T h e l e a s t o n e c a n s a yi s t h a t e x p o s u r e t o r e p e a t e d e l e c t r i c s h o c k s c a n p r o d u c ed e a t h a n d m y o c a r d i a l p a t h o l o g y in s o m e s q u i r r e l m o n k e y s( b u t, t h e m y o c a r d i a l p a t h o l o g y d o e s n o t s e e m t o c o n t r i b u t et o d e a t h , b e c a u s e a l t h o u g h i t c o u l d b e b l o c k e d b y b e t a -r e c e p t o r b l o c k a d e , d e a t h s t il l o c c u r r e d [ 23 ]) . T h a t t h i s e f f e c to f s t r e s s m a y b e s p e c i e s - s p e c i f i c is s u g g e s t e d b y t h e f a c t t h a tr h e s u s m o n k e y s o n e q u a l l y d e m a n d i n g [1 3] o r e v e n m o r ed e m a n d i n g s c h e d u l e s [ 9 0 ] d i d n o t d i e .T o s u m m a r i z e , w h e n t r e e s h r e w s , b u t n o t m i c e . a re

a l l o w e d b r i e f p e r i o d s t o f ig h t , t h e d e f e a t e d t r e c s h r e ~ d i e s .I f , a l t e r t h e i n it ia l v i c t o r y , t h e a n i m a l s a r e a l l o w e d t o r e m a i nw i t h e a c h o t h e r , t h e d e f e a t e d a n i m a l s o o n d i e s . S i m i l a re x a m p l e s o f s u d d e n d e a t h o c c u r i n w il d N o r w a y r a t s, s q u i r-r e l m o n k e y s a n d r a r e l y in s w i n e . W h e n a n i m a l s a r e c r o w d e da n d c o m b a t i v e , m i c e b e c o m e h y p e r t e n s i v e , c h i c k e n s d e -v e l o p c o r o n a r y a r t e r y d i s e a s e a n d r a b b i t s d e v e l o p c a r -d i o m y o p a t h y ; s w i n e a r e p r o t e c t e d b y t h is m a n e u v e r , a n dr a t s s h o w i n c o n s i s t e n t e l e v a t i o n s i n b l o o d p r e s s u r e . T h i s r e -v i e w s u g g e s t s t h a t m a m m a l s r e s p o n d t o a c u t e s t r e s s in as p e c i e s - s p e c i f i c p a t t e r n : S o m e s p e c i e s d i e f o r u n k n o w n r e a -s o n s w h e n c o n f r o n t e d w i t h a n a c u t e s t r e s s o r a n d o t h e r s d i eo f r e c o g n i z a b l e d i s e a s e s u c h a s r e n a l f a i l u r e o r c a r -d i o m y o p a t h y : o t h e r s , s u c h a s rh e s u s m o n k e y s [ 1 3 .9 0 ] a n db a b o o n s [ 13 ] s h o w a d a p t a t i o n r e g a r d l e s s o f d i s e a s e . T h en e x t q u e s t i o n i s w h e r e i n t h i s s p e c t r u m h u m a n b e i n g s l i e .

STRESS AND DISEASE IN HEALTHY HUMAN ST h e h e a d i n g o f t h i s s e c t i o n is i n h e r e n t l y a p a r a d o x . W h e nd i s e a s e e x i s t s , th e p a t i e n t i s o b v i o u s l y n o t h e a l t h y . T h e r e a r e

t w o w a y s t o d e a l w i t h t h i s p r o b l e m . F i r s t , o n e m a y r e v i e wt h o s e r e p o r t s in w h i c h d e a t h o r s e v e r e s ig n s o f d i s e a s e o c c u rs u d d e n l y . T h e s e c o n d t a c k i s t o r e v i e w t h o s e e p i d e m i o l o g i -c a l s t u d i e s w h i c h h a v e f o c u s e d o n t h e e f f e c ts o f s t r e s s o nl a r g e p o p u l a t i o n s o f y o u n g , a n d b y i n f e r e n c e , h e a l t h yp e o p l e .A r e v i e w o f t h e l i te r a t u r e s h o w s a n u m b e r o f c a s e r e p o r t si n w h i c h s e v e r e e m o t i o n a l s t r e s s p r e c i p i t a t e s p o t e n t i a l l y l e t -h a l c a r d i a c a r r h y t h m i a s . U n f o r t u n a t e l y , e v a l u a t i o n o f t h eh e a r t w a s n o t d e t a i l e d e n o u g h t o g u a r a n t e e t h e c o n c l u s i o nt h a t t h e h e a r t w a s f r e e o f d i s e a s e , o r t h e a s s u m p t i o n w a sm a d e t h a t l o n g - t e r m r h y t h m a b n o r m a l i t ie s w e r e d u e t o e m o -t i o n a l s ta t e r a t h e r t h a n t o s o m e f o r m o f c a r d i a c a b n o r m a l i t y ,F o r e x a m p l e , H a r v e y a n d L e v i n e h a v e r e p o r t e d t h e c a s e o f a2 9 y e a r o l d w o m a n i n w h o m f e a r p r o d u c i n g s t i m u l i p r e c i p i -t a t e d e p i s o d e s o f v e n t r i c u l a r t a c h y c a r d i a [4 8 ]. I n a s im i l a rp a t i e n t s u b j e c t e d t o a n e x t e n s i v e d i a g n o s t i c e v a l u a t i o n , t h ee l e c t r o c a r d i o g r a m r e v e a l e d p r o l o n g a t io n o f t h e Q T i n t er v a lb e f o r e t h e s t a r t o f v e n t f i c u l a r f i b r i l la t i o n [1 2 91 . O t h e r w o r kh a s i n d i c a t e d t h a t t h is s y n d r o m e c a n p r e s e n t i n v a r i o u sf o r m s i n w h i c h t h e Q T i n t e r v a l ca n b e n o r m a l e x c e p t a t t h et i m e o f s t r e s s o r i s a b n o r n a l l y l o n g a t a l l t i m e s . T h i s l o n g Q Ts y n d r o m e i s a k n o w n r i sk f a c t o r f o r s tr e s s - p r e c i p i t a t e d s u d ,d e n d e a t h [ I 1 2] . S i m i l a r l y c a s e r e p o r t s e x i s t s h o w i n g t h a tp a t i e n t s w i th p u r p o r t e d l y n o r m a l h e a r t s m a y , w h e n s t r e s s e d .d e v e l o p a h o s t o f p a r a s y m p a t h e t i c - r e l a t e d a r r h y t h m i a s ( e .g . ,[ 1 0 , 7 8 , 1 1 1 ] ) . S i n c e t h e s e p a t i e n t s d i d n o t d i e ~ p a t h o l o g i ca s s e s s m e n t o f t h e ir h e a r t s w a s n o t d o n e .I n o n e e x t r e m e l y w e l l d o c u m e n t e d c a s e [ 7 3 ], a 39 y e a r o l dm a n w i t h a t o t a l l y n o r m a l h e a r t w a s r e p o r t e d t o h a v ee p i s o d e s o f s t re s s r e l a t e d v e n t r i c u l a r ta c h y c a r d i a . S u b s e -q u e n t l y , R e i c h e t a l. [ 10 5] r e p o r t e d t h a t o f a p a t i e n t p o p u l a -t i o n r e fe r r e d t o t h e m f o r a r r h y t h m i a c o n t r o l a n d n o t a b l e b yt h e f a c t th a t t h e i r a r rh y t h m i c e p i s o d e w a s p r e c e d e d b y a c u t ep s y c h o l o g i c a l d i s t u r b a n c e s , 11 o f 2 5 h a d n o d e m o n s t r a b l eh e a r t d i s e a s e . O f t h is g r o u p w e r e 9 w o m e n , y o u n g e r th a n 3 0y e a r s o f a g e .T o s u m m a r i z e , m a l i g n a n t c a r d i a c a r rh y t h m i a s a r e u n -u s u a l o c c u r r e n c e s i n y o u n g h e a l t h y p e o p l e . W h e n t h e y o c -c u r , t h e y s e e m t o d o s o m o r e i n w o m e n t h a n i n m e n . B u t ar e a s o n a b l e q u e s t i o n t o a s k i s if t h e h e a r t s o f p e o p l e l i k e t h e s ea r e r e a l l y n o r m a l . A p h y s i c i a n s a y s t h e h e a r t i s n o r m a l i f h i st e s t s d o n o t r e v e a l d i s e a s e , b u t o b v i o u s l y t h i s d e p e n d s o n t h ea c c u r a c y o f h i s d i a g n o s t i c m e t h o d s . I n f a c t . s u g g e s t i v e e v i-


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dence is now growing that young victims of sudden deathmay indeed have abnor mal hearts. O ne example of this is theprolonged QT syndrome. Recent work has supported thehypothesis that this syndrome is due to an imbalance ofsympathetic and parasympathetic innervatio n to the heart[112]. Indeed, sometimes the diagnosis can be made duringlife, but if a young person with this syndrome dies suddenlywithout an ECG ever having been done, an autopsy will notreveal any pathology. This per son will be said to have had a"normal" heart .Another example concerns patients with typical anginalpain but diagnostically normal hearts. Recent work by Mas-eri e t a l . [77] shows that cor onary vasospasm may be elicitedin such patients and that the outcom e of this vasospasm maybe dangero us arrhythmia s or myocardial infarction; the rea-son for this vasospasm is currentl y unknow n, but the impor-tant thing is that the vessels of such people are clearly notnormall y innerva ted. Final ly, other possibilities that are nowknown to occur are the existence of heart disease in youngpeople that is either impossible [57] or extre mely difficult[76] to diagn ose in life. This an alysi s leads one to be c autio usin suggesting that serious heart disease can occur whenpeople with truly normal hearts are stressed.

Additional evidence does exist to indicate that stress, perse, does not necessarily increase the incidence of disease inlarge populations of people. Fo r example, reports exist fromconc entra tion camp inmates (at a time when they were notsubjected to physical deprivatio n or stress) indicating thathealth actually improved after they had been removed fromtheir job and pla ced in the cam p [132]. Similarly Hinkle e t a l .[54] prospectively studied the health patterns of a numbe r ofgroups of refugees from the Hungarian revolution of 1956.Despite this upheaval, the people reported an improvementin their general health and well-being in most instances.Based on several decades of prospective studies correlatinglife stresses with disease onset, Hinkle [53] came to the fol-lowing conclusion: Assuming a relatively constant physicalenvironment, "'exposure to culture change, social change,and change in interpersonal relations may lead to a signifi-cant change in health if (a) a person has preexisting illness orsusceptibility to illness, and (b) he perceives the change asimportant to him ." Thus, As Rapkin and Struening conclude[97]: "Exposure to stressors alone is almost never a suffi-cient explanation for the onset of illness in ordinary humanexperience."

STRESS AND DISEASE IN HUMANS WITH UNDERLYINGOVERTORCOVERT DISEASEBoth in an effort to keep this review managea bly long andbecause of a paucity of good data relating stress to the onsetof non-cardiac disease, this section will focus on the role ofstress in the ini tiation of symptom s in patients with heartdisease. But here, again for manageability, I will review onlythe eviden ce for stress being an acute caus ative factor in theonset of cardiac symptoms (either myocardial infarction orarrhythmia). If interested, the reader can turn to one of anum ber of reviews that lay out the evidence that psychoso-cial factors may play a role over a long period of time insensiti zing people to devel op cardiac d isease [20, 43, 59].Historically, medicine seems to progress in an orderlyway. First, an interesting relation or pheno meno n is reportedin a series of case reports. Next, someone sees a unifyingconcept between these case reports and writes a review.

Then, the epidemiologists take ove r and initially do retro-

.QRS ComplexR s R P ~ , j ~ T W o v e /3 .~VT

/h____/ 'x_

V F

FIG. 3. The top row depicts a normal electrocardiographic tracewith a regular sinus rhythm (RSR). In the second line, a bizarre andlong duration beat occurs prematurely. This is due to firing of anirritable ventricular ectopic focus and is called a ventricular prema-ture contraction (VPC). When these occur frequently and from morethan one focus, they indicate significant risk for sudden death. WhenVPCs occur sequentially, the arrhythmia is called ventriculartachycardia (VT). This is an unstable arrhythmia which can oftendegenerate into ventr icular fibrillation (VF). VF reflects chaoticventricular activity of a dysnergic type that does not support normalblood pressure.

spective studies analyzing the phenomenon of interest.Then, they do prospective studies. And, finally, wheneverpossible, an effort is made to study the phe nome non directlyin the laboratory. In fact, this is exactly the way o ur under-standing of the relation between stress and arrhythmia orsudden death has evolved.Before detailing this information, a brief digression intoelectrocardiography is essential in order to know what hap-pens in the heart of the usual sudden death victim. Figure 3shows a schematic of the normal electrocardiogram in reg-ular sinus rhythm (RSR). The P wave reflects normal atrialdepolarization, the QRS norma l ventricula r depolarizationand the T wave ven tricula r repolarization. On the next line,following a normal beat we see a prematur e, bizarre appear-ing depolarization. This is a ventricular premature contrac-tion (VPC) and is a sign of an irritable focus somewhere inthe ventricle. The next line portrays a series of sequentialVPCs; this arrhythmia is known as ventricul ar tachyca rdia(VT) and is dangerous because it frequently degenerates toventric ular fibrillation (VF), which reflects chaotic ventri cu-lar activity which is unable to maintain a normal blood pres-sure. VT and VF are the terminal rhythms often found inpeople succumb ing to the sudden death syndrom e. Fo r thoseinterested in further information on the "sudde n death"syndrome, several behaviorally oriented reviews are avail-able [71,85].

With this background, we can t urn to the literature. Caseshave been reported of people with coronary artery disease


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5 16 N A I - E L S ( I N

h a v i n g t h e o n s e t o f l if e th r e a t e n i n g v e n t r i c u l a r a r r h y t h m i a sa f t e r a n a c u t e e m o t i o n a l s t r e s s ( e . g . , [ 75 ]) . R e g e s t e i n [ 1 0 4]r e p o r t e d o n a g r o u p o f p a t i e n ts i n w h o m e m o t i o n a l u p s e tp r o d u c e d a r r h y t h m i a s a n d r e v i e w e d t h e r e l a t i o n s h ip b e -t w e e n p s y c h o l o g i c a l u p s e t a n d a r r h y t h m i a s . S i m i l a r ly , in h i sr e v i e w o f s u d d e n d e a t h d u r i n g p s y c h o l o g i c a l s t r e ss , E n g e l[ 30 ] n o t e d a n u m b e r o f r e p o r t s i n w h i c h p e o p l e w i t h h e a r td i s e a s e w e r e s a i d to s u c c u m b d u r i n g e m o t i o n a l a r o u s a l . A ne x a m p l e o f th i s w a s r e p o r t e d f o r a g r o u p o f p a t i en t s s h o r t lya f t e r s u s t a i n i n g h e a r t a t t a c k s . O f t h e 3 9 p a t i e n t s w h o d i e d , 6d i d s o i m m e d i a t e l y a f te r w a r d r o u n d s - - a n e v e n t i n t he l if e o ft h e p a t i e n t t h a t is t h o u g h t t o p r o d u c e a n x i e t y [ 58 ]. A n o t h e rs t u d y n o t e s t h a t o f 17 p a t i e n t s i n a c o r o n a r y c a r e u n i t a t t h et i m e o f t h e d e a t h o f a n o t h e r p a t i e n t , 1 3 s h o w e d d e t e r i -o r a t i o n s i n t h e i r m e d i c a l s t a t e , in c l u d i n g w o r s e a r r h y t h m i a s ,m o r e p a i n o r c a r d i a c a r r e s t [ 1 3 1 ]. A f in a l s t u d y r e p o r t e ds i m i l a r c l in i c a l d e t e r i o r a t io n a c c o m p a n i e d b y e m o t i o n a lu p s e t f o r a g r o u p o f p a t i e n t s f o l l o w i n g a b r u p t t r a n s f e r o u t o ft h e c o r o n a r y c a r e u n i t; t h e s e c o m p l i c a t i o n s w e r e r e d u c e d i na n o t h e r g r o u p o f p a t ie n t s b y p r e p a r i n g t h e m f o r t h e t r a n s f e ra n d i n s u r i n g c o n t i n u i t y o f c a r e b y t h e i r d o c t o r s a n dn u r s e s [ 6 5 ] .S e v e r a l r e t r o s p e c t i v e s t u d i e s h a v e n o t e d a n i n c r e a s e d i n -c i d e n c e o f e i t h e r p h y s i c a l [ 39 ,4 4 ] o r p s y c h o l o g i c a l [ 62 ,1 2 4 ]s t r e s s j u s t p r e c e d i n g t h e o c c u r r e n c e o f a c a s e o f s u d d e nd e a t h . M y e r s a n d D e w a r [8 3] r e p o r t e d t h a t 2 3% o f s u d d e nd e a t h v i c t im s h a d e x p e r i e n c e d a s i g n if i ca n t d e g r e e o f p s y -c h o l o g i c a l s t r e s s i n t h e 3 0 m i n b e f o r e d e a t h a s c o m p a r e d t o8 % o f a n o t h e r g r o u p s u s t a in i n g n o n - l e t h a l m y o c a r d i a l i n f ar c -t i o n s ; R i s s a n e n e t a l . [1 08 ] d i d a s i m i l a r r e t r o s p e c t i v e s t u d ya n d f o u n d t h e s a m e r e l a t i o n w i t h a c u t e s t r e s s. O n e o f t h ep r o b l e m s w i t h m o s t s u c h s t u d i e s i s t h a t h i s t o r y i s c o l l e c t e dr e t r o s p e c t i v e l y a n d ( o b v i o u s l y ) n o t fr o m t h e s u d d e n d e a t hv i c t im . T h u s t h e v a l u e o f t h e s t u d y o f T r i c h o p o u l o u s e t a l .[1 24 ] w h o s h o w e d a n i n c r e a s e d i n c i d e n c e o f d e a t h f o r p a -t i e n t s w i t h c a r d i a c d i s e a s e b u t n o t f r o m o t h e r i l l n e s s e s fo l -l o w i n g a m a j o r e a r t h q u a k e i n A t h e n s i n 1 9 81 . A n o t h e r h e l p -f u l s t u d y i s t h a t o f R e i c h e t a l . [ 10 5] w h o d i d a r e t r o s p e c t i v es t u d y o f 1 17 p a t i e n t s w h o s u r v i v e d p o t e n t i a l l y l e t h a l c a r d i a ca r r h y t h m i a s . O f t h e 9 6 p a t i e n t s w h o h a d d i a g n o s a b l e h e a r td i s e a s e , 14 g a v e a h i s t o r y o f i n t e n s e p s y c h o l o g i c a l d i s t u r -b a n c e o c c u r r i n g i n th e 2 4 h r p r i o r to t h e a r r h y t h m i c e p i s o d e .T h e p r e d o m i n a n t a f f e c t a s s o c i a t e d w i t h t h e p s y c h o l o g i c a ld i s t u r b a n c e w a s a n g e r . I n a f a s c in a t i n g r e p o r t w h i c h w o u l dh a v e w i d e s p r e a d c o n s e q u e n c e s i f i t w e r e f o u n d t o b e g e n e r -a l i z a b l e , W o l f [1 31 ] w a s a b l e t o u s e t h e p r e s e n c e o f d e p r e s -s i o n a n d d i s s a t i s f a c t i o n w i t h l i fe t o p r e d i c t w h i c h o f t h e c o r -o n a r y p a t i e n t s i n t h e r a t h e r s m a l l g r o u p h e w a s s t u d y i n gw o u l d s u c c u m b t o m y o c a r d i a l i n f a rc t i o n . M o r e p r o s p e c t i v es t u d i e s o f t h is t y p e w o u l d b e v e r y h e l p f u l i n f u r t h e r e v a l u a t -

i n g t h e p s y c h o s o m a t i c c o m p o n e n t o f t h e s u d d e n d e a t h s y n -d r o m e .A n o t h e r e p i d e m i o l o g i c a l t a c k t h a t h a s b e e n t a k e n t o e v a l -u a t e t h e r e l a ti o n b e t w e e n s u b a c u t e s t r e s s a n d d e a t h d u e t oh e a r t d i s e a s e t r a c k s r a t i n g s o f li f e s t r e s s o v e r t i m e . T h e s es t u d i e s h a v e t h e a d v a n t a g e o f a ll o w i n g a p r o s p e c t i v e e v a l u a -t i o n o f t h e h y p o t h e s i s t h a t s t r e s s c a n t r i g g e r a c o r o n a r ye v e n t . T h e f i r st o f t h e s e i n t h is s e r i e s , h o w e v e r , w a s a r e t r o -s p e c t i v e , u n c o n t r o l l e d s t u d y o p e n t o a ll t h e b i a s e s o f f a u l t yr e c a l l . R a h e e t a l . [9 8] i n t e r v i e w e d s p o u s e s o f p e o p l e d y i n gs u d d e n l y o f c o r o n a r y a r t e r y d i s e a s e a n d f o u n d a s i g n if i ca n ti n c r e a s e o f l i fe c h a n g e u n i t s i n t h e 6 m o n t h s b e f o r e d e a t h a sc o m p a r e d t o e a r l i e r t i m e s p o c h s . U s i n g s i m i l a r r e t r o s p e c t i v ei n t e r v ie w i n g t e c h n i q u e s , G r e e n e e t a l . [ 45 ] s u g g e s t e d t h a t t h e

m a j o r i t y o f s u d d e n d e a t h v i c t im s h a d b e e n d e p r e s s e d s h o r t ly

b e f o r e t h e i r d e m i s e a n d t h e n h a d b e e n a c u t e l y a r o u s e d b y l i fes t r e s s e s p r e c i p i t a t i n g a n x i e t y o r a n g e r . I n a p r o s p e c t i v e , u n -c o n t r o l l e d s u r v e y , T h e o r e l l e t a l . [ 1 2 2 ] a s k e d n e a r l y 9 , 1 0 0c o n s t r u c t i o n w o r k e r s t o a n s w e r a q u e s t i o n n a i r e c o m p r i s e do f p s y c h o s o c i a l q u e s t i o n s , i n c l u d i n g li f e - c h a n g e it e m s , f o rt h e p r e c e d i n g y e a r . A l t h o u g h t h e l i f e - c h a n g e r a t in g s c a l e d idn o t p r e d i c t f u t u r e m y o c a r d i a l i n f a r c t io n s , o n e s p e c i f i c li fe -c h a n g e , n a m e l y i n c r e a s e d r e s p o n s i b i l i t y a t w o r k , p r e d i c t e d as i g n i f i c a n t b u t l o w ( 1 0% ) n u m b e r o f n e a r - f u t u r e M I s . I m p o r -t a n t l y , t h e c o r r e l a t i o n b e t w e e n d i s r u p t i v e l i fe c h a n g e s a n di m m i n e n t c o r o n a r y d e a t h w a s m u c h b e t t e r in a f o l l o w - u ps t u d y o f p a t i e n ts w h o h a d e x p e r i e n c e d a d o c u m e n t e d M I i nt h e p a s t [ 1 23 ]. A s c o m p a r e d t o p o s t - i n f a r c t i o n p a t i e n t s w h os u r v i v e d t h e s t u d y p e r i o d , p a t i e n t s s u c c u m b i n g t o h e a r t d i s -e a s e s h o w e d a s i g n i f ic a n t b u i l d u p i n l if e c h a n g e s w h i c hp e a k e d a b o u t o n e y e a r p r i o r t o d e a th .

S t u d i e s s u c h a s t h e a b o v e h a v e m a d e i t c l e a r t h a t l o ss o f as p o u s e i s o n e o f th e m o s t h i g h l y s t r e s s f u l e v e n t s t h a t c a no c c u r t o a p e r s o n . B e c a u s e o f t h i s . a n u m b e r o f s t u d ie s h a v eb e e n d o n e i n a n e f f o r t t o r e l a t e s u d d e n d e a t h w i t h t h e g r i e fd u e t o s u c h a m a j o r l o s s . P a r k e s e t , l . [ 95 ] f o l l o w e d a g r o u po f w i d o w e r s w h o w e r e 5 5 y e a r s o f a g e o r o l d e r. T h e y f o u n dt h a t i n t h e f i r st 6 m o n t h s o f b e r e a v e m e n t , t h e d e a t h r a t e w a s4 0 % a b o v e w h a t m i g h t b e e x p e c t e d f o r m a r r i e d m e n o f th es a m e a g e . T h e r e a f t e r , t h e m o r t a l i t y r a te f e l l t o t h a t o f t h em a r r i e d m e n . H e l s in g e t a l . [ 49 ] f o u n d s i m i l a r s e n s i t i z a t i o nf o r w i d o w e r s 5 5 t o 7 4 y e a r s o f a g e ; t h i s r e l a ti o n w a s n o tf o u n d f o r w i d o w s . T h e y a l s o l e a r n e d t h a t m o r t a l i t y r a t e s fe l lf o r w i d o w e r s w h o r e m a r r i e d . A n o t h e r s t u d y , d o n e o nw o m e n w h o s u d d e n l y d i e d o f c a r d i a c d i s e a s e , s h o w e d t h a tv i c t i m s w e r e 6 t i m e s a s l i k e l y t o h a v e e x p e r i e n c e d t h e d e a t ho f a ~ ' s i g n i fi c a n t o t h e r " w i t h i n t h e 6 m o n t h s p r i o r tod e m i s e [ 2 6 ] .T h e s e e p i d e m i o l o g i c a l s t u d i e s p r o v i d e r a t h e r c o n v i n c i n ge v i d e n c e t h a t a c u t e o r s u b a c u t e p s y c h o s o c i a l s t re s s c a np r e c i p i t a t e p o t e n t i a l l y l e t h a l c a r d i a c a r r h y t h m i a s a n d / o rm y o c a r d i a l in f a r c t i o n i n p a t i e n t s w i t h o v e r t d i s e a s e . T h eo t h e r t h i n g t h a t s h o u l d b e u n d e r s t o o d i s t h a t t h e s e s t u d i e ss u g g e s t t h e s a m e s e n s i t i z a t i o n f o r p e o p l e w i t h c o v e r t d i s -e a s e . T h e q u e s t i o n t h a t m u s t b e c o n s i d e r e d i s w h y a r e e l-d e r l y w i d o w e r s s e n s i t i z e d b y l o s s o f t h e i r w i v e s w h i l ey o u n g e r o n e s a r e n o t . T h e i n f e r e n c e I d r a w f r o m t h e s es t u d i e s i s t h a t t h e e l d e r l y h a v e c o v e r t h e a r t d i s e a s e . T h i si n f e r e n c e i s b a s e d o n t h e w e l l k n o w n f a c t t h a t a r t e r i o s c l e r o -t i c d i s e a s e i s k n o w n t o b e g i n i n t h e v e s s e l s o f h e a l th y 2 0 y e a ro l d A m e r i c a n m e n [ 31 ]. T h u s , b y l a t e m i d d l e ag e , a p p r e c i -a b l e a r t e r i o s c l e r o s i s m a y e x i s t e v e n t h o u g h t h e m a n m a yh a v e n o s y m p t o m s . T h i s i n t e r p r e t a ti o n i s s t r e n g t h e n e d b yt h e r e c e n t r e p o r t t h a t V P C s a r e u n u s u a l i n th e y o u n g a n di n c r e a s e m o n o t o n i c a l l y b o t h i n t e r m s o f i n c i d e n c e a n d f r e-q u e n c y w i t h i n c r e a s i n g a g e [ 6 6] ; t h i s la t t e r r e p o r t i s p a r t i c u -l a r l y im p o r t a n t i n t h a t d a t a w e r e c o l l e c t e d o n l y f r o m p a t i e n t sw h o h a d n o e v i d e n c e o f h e a r t d i se a s e a s a s s e s s e d b y a c o m -p l e t e d i a g n o s t i c c a r d i o l o g i c b a t t e r y .F i n a l l y , d a t a e x i s t to i n d i c a t e t h a t w h e n p e o p l e w i t h h e a r td i s e a s e a r e s t r e s s e d b y e x p e r i m e n t a l m a n i p u l a t i o n , f r e -q u e n c y o f a b n o r m a l b e a t s i n c r e a s e s c o n s i d e r a b l y . T a g g ar t e ta l . [ 12 1] r e p o r t e d t h a t e l e c t r o c a r d i o g r a p h i c c h a n g e s a n ds y m p t o m o n s e t o c c u r r e d i n c a r d i a c p a t i e n t s w h i l e d r i v i n gt h e i r c a r s i n b u s y c i t y t r a ff i c a l o n g f a m i l i a r r o u t e s ; t h e s ef i n d i n g s d i d n o t o c c u r i n p e o p l e w i t h n o r m a l h e a r t s . S i m i -l a r l y , R o s e [1 09 ] h a s m o n i t o r e d h e a r t r h y t h m o fp o s t c o r o n a r y p a t i e n t s w h o w e r e s p e c t a t o r s a t e m o t i o n a l l ya r o u s i n g s p o r t s e v e n t s . H e n o t e d t h a t i t w a s n o t u n u s u a l f o rt h e s e p e o p l e t o e x h i b i t o n s e t o f a r r h y t h m i a s o r i n c r e a s e s in


7/17


a r r h y t h m i a fr e q u e n c y a t th e s e t i m e s . S t e v e n s o n e t a l . [ 119]w e r e t h e f i rs t g r o u p t o s h o w t h a t a r r h y t h m i a f r e q u e n c y c o u l db e i n c r e a s e d i n c a r d i a c p a t ie n t s b y d i s c u s s i n g a n x i e t y -p r o v o k i n g i s s u e s w i t h th e m . M o r e r e c e n t l y , L o w n a n d D e -S i l v a [7 2] h a v e r e p o r t e d t h a t v e n t r i c u l a r p r e m a t u r e b e a t f r e -q u e n c y i n c r e a s e d i n 11 o f 1 9 c a r d i a c p a t i e n t s d u r i n g s u c hs t r e s s e s. I n c o n t r a s t w h e n a u t o n o m i c n e r v o u s f u n c t i o n w a ss t i m u l a t e d b y l a b t e s ts , o n l y 1 p a t i e n t s h o w e d a n i n c r e a s e i na r r h y t h m i a f r e q u e n c y . T h i s s u g g e s t s th a t t h e p a t t e r n o f a u -t o n o m i c a r o u s a l t h a t i s p r o d u c e d i n t h e r e a l li f e a n x i e t y -p r o v o k i n g s i t u a t i o n i s w h a t i s i m p o r t a n t i n i n c r e a s i n g a r -r h y t h m i a s i n t h e s e p e o p l e . D o n l o n e t a l . [28 ] , i n a s im i l a rv e i n , h a v e s h o w n t h a t f o r a p a r t i c u l a r p a t i e n t , p s y c h o l o g i c a ls t r e ss m a y i n c r e a s e a r r h y t h m i a s w h i l e p h y s i c a l s t re s s d o e sn o t .C O N C L U S I O N F R O M L I T E R A T U R E R E V I E W

A c u t e s t r e s s c a n p r e c i p i t a t e l et h a l o r p o t e n t i a l l y le t h a lc a r d i a c a r r h y t h m i a s i n th e p e r s o n w i t h e i t h e r o v e r t o r c o v e r th e a r t d i s e a s e . B u t , s i n c e th i s c o n c l u s i o n i s b a s e d i n p a r t o ni n f e r e n c e , i t w o u l d b e i m p o r t a n t t o t e s t it e x p e r i m e n t a l l yu s i n g a n i m a l s w i t h a p r e d i s p o s i t i o n t o h e a r t d i s e a s e .A N I M A L M O D E L S - - T H E C A R D IO M Y O P A T H 1C H A M S T E R

T h e f i r s t m o d e l w e c h o s e t o s t u d y u s e d t h e c a r-d i o m y o p a t h i c h a m s t e r ( C M H ) a s s u b j e c t [1 20 ]. T h i s a n i m a li n h e r it s i t s c a r d i a c d i s e a s e v i a a n a u t o s o m a l r e c e s s i v e t r a it .A l t h o u g h t h e a n i m a l h a s p a t h o l o g i c a l a b n o r m a l i t i e s i n i t sh e a r t b y 3 m o n t h s o f a g e , th e h a m s t e r a p p e a r s w e l l u n t i l i t i so v e r a y e a r o l d . T h e n , o v e r t h e n e x t m o n t h s , t h e a n i m a ls t o p s g r o o m i n g , a p p e a r s i ll w it h a c c u m u l a t i o n s o f s u b -c u t a n e o u s f l ui d , a n d t h e n d i e s - - p r e s u m a b l y d u e t o h e a r tf a i lu r e . O u r i d e a w a s t o t a k e g r o u p s o f C M H a n d h e a l t h yh a m s t e r s ( H H ) a n d s u b j e c t h a l f o f th e m t o s t r e s s ; t hi s w a s t ob e d o n e w h e n t h e h a m s t e r s w e r e 6 m o n t h s o l d a n d t h u sa p p e a r e d t o t a l l y n o r m a l . O u r p l a n w a s t o c h a n g e s t r e s s o r sf r o m d a y t o d a y i n o r d e r t o a v o i d t h e d e c r e m e n t i n s t r e s sr e s p o n s e t h a t a c c o m p a n i e s r e p e a t e d e x p o s u r e to t h e s a m es t r e s s o r [ 92 ]. O n D a y 1 , h a m s t e r s i n t h e s t r e s s g r o u p w e r es u b j e c t e d t o c o l d - i m m o b i l i z a t io n f o r 2 h r. O n D a y 2 , e a c hs t r e s s e d h a m s t e r w a s g i v e n g r i d s h o c k a t a r a t e o f 1 p e r r a inf o r an h o u r . O n D a y 3 , h a m s t e r s w e r e g i v e n g r i d sh o c k a s ag r o u p ; t h is p r o c e d u r e e l i c it e d a g r e s s i v e d i s p l a y , re a r i n g a n db o x i n g , b u t t h e r e w a s n o b i t in g o r o b v i o u s p h y s i c a l w o u n d s .I m m e d i a t e l y t h e r e a f te r , h a m s t e r s w e r e s u b j e c t e d t o s u p i n ec o l d - i m m o b i l i z a ti o n f o r 2 .5 h r . O n D a y 4 , h a m s t e r s w e r e n o td i s t u r b e d , a n d t h e n o n D a y 5 , h a m s t e r s w e r e t r e a t e d a s o nD a y 3 . H a m s t e r s i n t h e c o n t r o l g r o u p s w e r e h a n d l e d a t th eb e g i n n i n g a n d e n d o f e a c h s t r e s s s e s s io n .A b o u t 6 0 h r a f t e r t h e l a s t s tr e s s s e s s i o n , h a m s t e r s w e r es a c r i fi c e d . F i g u r e 4 s h o w s t h e m o s t g e r m a n e r e s u l ts . F i v e o ft h e 6 s t r e s s e d C M H h a m s t e r s s h o w e d o b v i o u s f l u id r e te n t i o n( i .e . , d e p e n d e n t e d e m a ) i n d i c a t iv e o f c o n g e s t i v e h e a r t f a i l-u r e . N o n e o f t h e a n i m a l s in t h e o t h e r 3 g r o u p s d e m o n s t r a t e dt h i s . M o r e o v e r , s t r e s s e d C M H h a m s t e r s s h o w e d s i g n i f i -c a n t l y m o r e f l u i d w i t h i n t h e i r b o d y c a v i t i e s t h a n d i d t h eh a m s t e r s i n t h e o t h e r 3 g r o u p s ; t h i s s o r t o f f l u i d r e t e n t i o n i sa l s o i n d i c a t i v e o f c o n g e s t i v e h e a r t f a i lu r e . T h u s , t h i s e x p e r i -m e n t s h o w s t h a t h an d l i n g C M H h a m s t e r s o r s u b j e c t in gh e a l t h y h a m s t e r s t o p h y s i c a l s t re s s h a s n o h e a l t h c o n s e -q u e n c e s . I t i s o n l y w h e n h a m s t e r s w i t h c o v e r t d i s e a s e a r es t r e s s e d t h a t t h e p o t e n t i a l ly l e th a l s y n d r o m e o f c o n g e s t iv eh e a r t d i s e a s e d e v e l o p s . W e a r e c u r r e n t l y d o i n g o t h e r e x p e r -i m e n t s t o l e a rn h o w s t r e s s p r o d u c e s t h e s e e f f e c ts .

0.20

E 0 . 1 5I . - -1 -( . . 9i , i 0.10: : ). JI t .z 0.0 5I . . U

I

i

C M H H HS T R E S S E D

i :C M H H H

N O T S T R E S S E DFIG . 4 . A ve rage w e igh t o f fl u id abso rbed on sponges f rom thepleural and abdominal cavi t ies ( f rom [120]) . Note that the CMHstressed grou p had s igni f icant ly more f lu id than th e other group s .The nu m ber s w i th in each ba r r ep re sen t t he num ber o f an im a l s show -ing over t hear t fa i lure per the to ta l number wi thin that group.

A N I M A L M O D E L S - - P S Y C H O S O M A T I C D IG I T A L I S T O X I C IT YT h e o t h e r m a j o r m o d e l w e a r e p u r s u i n g i n o u r l a b o r a t o r yu s e s d i g i t a l i s t o p r e d i s p o s e t h e o t h e r w i s e n o r m a l h e a r t t od e v e l o p a r r h y t h m i a s . I n t h e U n i t e d S t a t e s , d i g i t a l is i s a v e r yc o m m o n l y p r e s c r i b e d d r u g . I t i s u s e d a s a c a r d i o t o n i c tot r e a t c o n g e s t i v e h e a r t f a i l u r e [8 1 ]. T h e p r o b l e m w i t h t h e d r u gi s t h a t t h e r e i s a v e r y n a r r o w z o n e b e t w e e n t h e r a p e u t i c e ff i -c a c y a n d t h e d r u g ' s p o t e n t i a l ly l e th a l s i d e - e ff e c t o f p r o d u c i n gs e r i o u s v e n t r i c u l a r a r r h y t h m i a s . I n fa c t , a h i g h p e r c e n t a g e o fp e o p l e t a k i n g th i s d r u g h a v e d i g i t a l i s - t o x i c a r r h y t h m i a sw i t h o u t k n o w i n g i t [ 9] . S i n c e b l o o d l e v e l s o f t h e d r u g h a v en o t p r o v e n u s e f u l p r e d i c t o r s o f d i g i ta l i s c a r d i o t o x i c i t y [ 1 1 7] ,e f f o r t s h a v e b e e n m a d e t o d e f in e t h o s e f a c t o r s t h a t p r o d u c ed i g i t a l is t o x i c i t y a t n o r m a l d o s e a n d p l a s m a l e v e l s . T h e s e

i n c l u d e t h y r o i d a n d r e n a l d y s f u n c t i o n [1 17 ] a n d e l e c t r o l y t e o ra c i d - b a s e p r o b l e m s [ 8 1] . B e c a u s e d i g i t a l i s - to x i c a r r h y t h m i a so c c u r d u r i n g e x o g e n o u s i n f u si o n o f c a t e c h o l a m i n e s [8 1] o re n d o g e n o u s r e l e a s e d u e t o b r a i n s t i m u l a t i o n [ 3 2 ] , a n d b e -c a u s e b e h a v i o r a l t e c h n i q u e s [ 12 ] c a n a l t e r d i g i t a l i s - t o x i c a r -r h y t h m i a s , w e m a d e t h e h y p o t h e s i s t h a t p s y c h o l o g i c a ls t r e s s- - - w h i c h a l s o a c t i v a t e s a u t o n o m i c s y s t e m s - - - c o u l d a lt e rt h e t h r e s h o l d a t w h i c h a n a n i m a l s h o w e d d i g i t a l i s c a r -d i o t o x i c i t y .O u r f i r st t a s k w a s t o g a i n f a m i l i a r i t y w i t h t h e a n i m a l t h a tw o u l d s e r v e a s s u b j e c t f o r th e d i g i t a li s e x p e r i m e n t s . T h i sw a s t h e a d u l t , m a l e g u i n e a p i g , w h i c h , i n c o n t r a s t t o t h e r a tw h i c h i s n o t a b l y r e s i s t a n t t o t h e e f f e c t s o f d i g i t a l is , d e v e l o p sc a r d i a c a r r h y t h m i a s a t r e l a t i v e l y l o w d o s e s o f t h e d r u g . O u rp l a n w a s t o r e c o r d t h e e l e c t r o c a r d i o g r a m f r o m g u i n e a p i g s

w h i c h w e r e f r e e - r a n g i n g a n d w h i c h w e r e s u b j e c t e d t o i m -


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mobil izati on in orde r to see the effect o f this stress on thecardiac rhythm of these normal animals [86]. Abnorm al ven-tricular beats were unusual but occasionally seen in thefree-ranging guinea pig. During restraint, the incidence andmagnitude of ventricula r arrhythmias i ncreased significantly.At the time we did this experiment, we were impressed bythe fact that stress could induce ventric ular arrhythmias.However, in retrospect, even the worst appearing ar-rhythmias were self-limited and multiple ventricu lar ectopicfoci--which increase the probability of the arrhythmia de-generating into ventricular fibrillation--were most unusual.Moreover, on the mornin g after the overnight restraintstress, all the guinea pigs were healthy and had normal car-diac rhythms. Thus, we concluded that as in our monkeyexperiment reviewed above, stress would reliably produceevidence of disease, but the animal could cope with suchstress and would recuperate from its illness.Our next experiment was to combine immobilizationstress with intra peritonea l injections of ouabain , a fast actingdigitalis preparation [91]. We injected adult male guinea pigswith doses of the drug ranging from 150 to 225 mg/kg. Pigswere then placed back in their home cages for 45 min. Theywere then again removed from their home cages and werethen ran domly placed into one of 3 treat ment condition s: (a)back in home cage with food and water now removed; (b)into a novel caging env iron ment devoid of food and water; or(c) into restraint. Then guinea pigs were examined periodi-cally to determine whether or not the drug had produced alethal outcome.The dose-related toxicity of the drug was immediatelyobvious. No guinea pig that was injected with 150 mg/kg ofouabain died. And, for pigs given 200 or 225 mg/kg of oua-bain, no difference was found across the 3 treatments as tothe nu mbe r of pigs succu mbing to the drug. Ho weve r at the175 mg/kg dose, a sign ificant tre atme nt effect was seen:Whereas only 9% of the guinea pigs that were returned totheir home cage or were placed into novel cages died, 50% ofrestrained pigs died.The next experiment was designed to ascertain the effectof repeated stress sess ions [91]. Because significant differ-ences had not be en found between ho me cage and novel cagegroups at any of the doses in the acute experiments, thenovel cage condition was dispensed with. In this experimen t,pigs were either subjected to daily handling and IP salineinjection or to this plus immobilization for 4-5 hr. On thefifth such session, oua bain was substi tuted for saline. In con-trast to the lethal effect of acute stress, none of the re-peate dly re stra ined pigs died after receivin g the 175 mg/kgdose; the difference in mortality between acutely and re-peatedly stressed pigs was significant. The protection af-forded by repeated exposure to the stressor supports clinicaluse of desensitization or "flooding" techniques as therapeu-tic modalities for stress-related complains.Of major importance, here, is the fact that the stress ofacute restraint lessened the dose of ouabain needed toproduce its lethal side effects. This finding can be viewed asan outgrowth of the seminal work of Bajusz and Selye [5]who showed that the c ombina tion of fluorocortisol andsodium acetate can predispose an animal to develop cardiacdisease following the application of stress. However, thepertinence of that work to clinical medicine was unclearsince the comb inati ons of drugs used in those early studieswere seldom prescribed. This is not the case in this instancewhere the toxicity of a cardiac glycoside was studied. Thedata from this study indicate that e nviro nment al factors will

have to be considered in addition to changes in the internaimilieu when trying to explain individual differences in sen-sitivity to toxicity while taking constant doses of digitalis.More generally, our experiments indicate thai the conceptelucidated by Bajusz and Selye--that drug pretrcatment cansensiti ze an orga nism to devel op seriot, s disease whenstressed--is an important one which may well be germane inund erst and ing why disease begins when it doe~,The problem with the above study of course related to ouruse of restraint as a stressor. Although psychologists oftensuggest that restraint can be used as a model of acute psycho-logical stress, the physical component in this stressor is ob-vious. Thus, we began thinking about ways to develop aparadigm in which psychological factors could be divorcedfrom the physical.Our first effort to do this was limited by the hardware wehad available to record electrocardiograms. Using amplifiersin the standard laboratory polygraph, we found that we couldnot get c lean tracing s in the free ranging guine a pig. So weturned at first to a restraint model, but one in which theanimal had more room to move than in the method we usedabove [88]. The apparatus was a length of 4" diameter plasticpipe with a grid floor on the end of which was a panel with 3cue lights and a sonalert. The guinea pig was shaved andelectrocardiogram electrodes were placed on ils back andshock electrodes on its rump. The animals were then ran-domly assigned to a signal alone grou p o r a signal shockgroup. In the former, animals were confronted with a 60,75sec signal once every 5 min for 30 min. In the latter group,40% of these signals were accompanied by a 0.75 sec shockdelivered 60 sec after the start of the signal. Then, on aweekly basis, guinea pigs were given an IP injection of ona-bain and then were probed with the signal alone {i.e., shockwas never delivered on this probe day). Electrocardiogramswere recorded on this probe day and were analyzed to de-termine when in relation to the signal, digitalis-toxic cardiacarrhythmias began.Our hypo thesis in initiati ng these stu dies was that theprobability of arrhythmogenesis would be greater during asignal previously paired with shock than during it [88]. Wealso reasoned that in animals never subjected to shock, ar-rhythmogene sis would not relate to signal. The data matchedour expectations: In signal shock animals, arrhythmiasbegan significant ly more ofte n during the 60 sec signal periodthan during the preceding 60 sec (I.1+-0.3 and 0.4+0.2, re-spectively); in signal alone animals, arrhythmic episodeswere noted with similar rarity both before and during thesignal (0.3+0.2 and 0.3_+0.2, respectivelyJ. Moreover, acompariso n across the groups showed no significant differ-ence in percent of experiments showing arrhythmias prior tothe signal; in contrast, during the signal, the signal shockgroup showed a significantly higher frequency of onset ofarrhythmias than the signal alone group.Figure 5 shows an example of an elect rocardiogram froman animal with prior exposure to signal shock pairing. Lin e Ashows the pig's normal sinus rhythm. The arrow in line Bdepicts the start of the probe with the signal. By line C. someheart rate slowing is evident and, then, by line D, occasionalventric ular ectopic beats are seen. By lines E and F, theseabnormal beats are occurring in runs of 3 or more and thusfall into the category of ventricular tachycardia. In line G,the signal goes off+ and there after, the rh ythm gra dually re-turns to normal. It should be noted that this return to normalwas not common: usually, the digitalis-toxic arrhythmialasted for quite a while after initiation.


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STRESS, PREDISPOS ITION AND SERIOUS DISEAS E 519

A

C

. . . . . . . . . . . . . . . . .

: i i , . [ . . . . . . . . . . . . .

1 . liA Ua I..4-ta' l~ / .1 ~ !~ . IL aa a I . I. : I - - L _ ~t I - I " - ' J i l l. . . . : T ~ ) l r . . . . . . . ." ' i l l ' " : ' l - " i . . . . . " l

; - h i t . t: ~a_._I~_I~X,A,A_.L~ I . I, J,a L,4....i~.2, L - l / . l : J ,~ l . ~ . ~ t . ~ . j _ , . ! . l . 1 . I . ;~ I . I . J ~ - - t ~

k ' i " , i

FIG. 5. Electrocardiographic trace from a guinea pig with prior Pavlovian fear condi-tioning done on a "probe" day after ouabain injection (from [88]). Signals are deliveredbut shock never is. Regular sinus rhythm is seen in row A. The signal comes on (arrow)in row B. By row C, there is obvious heart rate slowing and an occasional VPC.Subsequently, the VPCs occur in sequential runs and are thus representative of VT.The CS is turned off at the arrow in G. In contrast to most guinea pigs which continueto exhibit digitalis-toxic arrhythmias, this animal 's rhythm gradually returned to nor-mal.

This experi ment was import ant in reiterating that stress inthe form of prior fear conditio ning could sensitize guinea pigsto develop digitalis toxic arrhythmias during the signal thatelicited the fearful state. But this paradigm really was unabl eto adequat ely separate physical from psychological factors inthe genesis of these arrhyth mias. An d, in fact, we found thatguinea pigs that were neve r shocked still developed digitalistoxicity prior to the fear-provoking signal with the same fre-quency as fear-conditioned animals. Thus, we reasoned thatthe physical stress of restraint which was still operative inthis design was sensitizing our control populati on to develo parrhythmias also.To deal with this possibility, we made a final apparatuschange. We were able to do this because of the availability ofan exte rnal filtering system which allowed us to collect rec-ognizable electrocardiographic records from free-rangingguinea pigs. The apparatus is depicted in Fig. 6. As can beseen, the guinea pig has been fitted with a belt which coversECG electrodes on the chest and shock electrodes on therump. With this apparatus, the pig is free to move about inthe experimental chamber. Since the chamber is housed

within a darkened, sound attenuated box, onset of the pilotlight signal is readily evident to the experimental subject.Electrodes are led away from the animal and out of thechamber via a commutator which also permits the adminis-tration of drugs.

The experimental design was similar to that in the laststudy. Here pigs were studied in 2 waves of pairs [87]. Fol-lowing a 10 min cont rol perio d, 30 sec light stimuli weredelivered on the average of once e very 3.3 min. For half theanimals (signaled shock), these stimuli were followed by arump shock 30% of the time. We chose this partial rein-forcement schedule because less extinction of visceral con-ditioni ng follows such sessio ns [93]. The othe r pigs (signalalone) were never shocked. Pigs constitutin g the secondwave did no t have cue lights illuminated during their trainingsessions. Ho wever, half of these ani mals (unsignaled shock)were shocked on the identical schedule as the signaled shockgroup. The re maining pigs were exposed to neith er cue lightsnor shocks (no stimuli).During training, guinea pigs were prepared with chronicindwelling venou s catheters and th en were i nfused intrave-


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5 2 0 N A T E L S ( ) N

FIG . 6 . A ppa ra tus u sed t o d i f f e r en t i a te phys i ca l fr om psycho log i ca l f ac to r s i n t he genes i s o f s t r e s s - i nduced d ig i t a li s tox i c i t y .E l ec t rodes ex i t v i a a h igh g r ade com m uta to r w h ich a l low s t he p ig t o m ove abou t f r ee ly in t he cham ber . The com m uta to r ha s a f lu idchanne l t o a l l ow in j ec t i on o f d rugs .

n o u s l y w i t h o u a b a i n o n a p r o b e d a y w h e n s i g n al s w e r e g i v e na s u s u a l b u t w h e n n o s h o c k w a s e v e r d e l i v e r e d . E C G w a sm o n i t o r e d t h r o u g h o u t t h e i n f u s io n p e r i o d , a n d t h e t i m e t ov e n t r i c u l a r ta c h y c a r d i a ( V T ) w a s a s c e r t a i n e d b y a c a r -d i o l o g i st w h o d i d n o t k n o w t h e e x p e r i m e n t a l h i s t o ry o f e a c ha n i m a l .S i n c e o u a b a i n w a s g i v e n b y i n f u s i o n , V T a l w a y s e v e n -t u a t e d . E C G a n a l y s i s re v e a l e d t h a t V T o c c u r r e d s i g n if i c an t l ye a r l i e r d u r i n g o u a b a i n i n f u s i o n i n t h e s i g n a l e d s h o c k g r o u p a sc o m p a r e d t o t h e s i g n a l a l o n e g r o u p . I n c o n t r a s t , t h e l a t e n c yt o V T f o r t h e u n s i g n a l e d s h o c k g r o u p w a s n o t d i f f e r e n t f r o mi t s n o s t i m u l i c o n t r o l s . M o r e o v e r , t h e t i m e f o r V T f o r t h es i g n a l e d s h o c k g r o u p w a s s i g n i fi c a n t ly e a r l ie r th a n t h e u n -s i g n a l e d s h o c k g r o u p ( s e e F i g . 7 ) .W e b e l i e v e t h is e x p e r i m e n t i s i m p o r t a n t f o r s e v e r a l r e a -s o n s . F i r s t , t h e e x p e r i m e n t m a k e s i t c l e a r th a t p s y c h o l o g i c a lf a c t o r s a l o n e c a n p l a y a r o l e i n t h e i n i t i a ti o n o f p o t e n t i a l l y li f et h r e a t e n i n g a r r h y t h m i a s c h a r a c t e r i s t i c o f d i g i t a li s t o x ic i t y .T h u s , a s u b j e c t t a k i n g " n o r m a l " a m o u n t s o f t h i s c o m m o n l yp r e s c r ib e d d ru g a n d p r e s u m a b l y h a v in g " n o r m a l " p l a s m al e v e l s o f th i s d r u g c a n d i s p l a y d i g it a li s t o x i c i t y w h e n p s y c h o -l o g i c a ll y s t r e s s e d . W e b e l i e v e t h e d a t a f r o m t h e s e e x p e r i -m e n t s h a v e c l i n i c a l r e l e v a n c e w h e n v i e w e d i n t h e c o n t e x t o f

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FIG . 7 . Av erag e time to V T for p igs wi th di fferent tra ining his tor ies( f rom [87]) . Note that sens i t iza t ion occurs only for the c lass ical lycondi t ioned group ( i . e . . those exposed to s ignal -shock pai r ing) .


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o l S a lin e A t ro p in e M e t h y l A t r o p .FIG . 8 . A ve rage t im e t o V T fo r p ig s exposed e i t he r t o s i gna l -shockpai r ing or to s ignals a lone ( f rom [16]) . No te that the sens i t iza t ionseen i n t he s a l ine t r ea t ed s i gna l - shock g roup i s abo l i shed by t r ea t -m en t s w i th bo th a t rop ine p r epa ra t i ons .

s i t iz e d th e h e a r t s o t h a t c o m p a r i s o n s b e t w e e n s h o c k a n dn o - s h o c k g r o u p s w o u l d b e i n a p p r o p r i a t e . S i n ce t h isp o s s i b i l i t y c a n b e e l i m i n a t e d b y t h e f a c t t h a t p i g s s u b j e c t e dt o u n s i g n a l e d s h o c k s h o w e d n o h a s t e n i n g t o o n s e t o f V T , i t i sc l e a r t h a t p s y c h o l o g i c a l s t r e s s alone i s s u f f ic i e n t t o p r o d u c et h e a r o u s a l r e s p o n s i b l e f o r t h e o n s e t o f t h e s e l e t h a l s id e e f -f e c t s o f d i g i t a l i s.I n t h in k i n g a b o u t t h is e x p e r i m e n t , o n e m i g h t w o n d e r w h yt h e e f f e c t w a s p r o d u c e d w i t h s i g n a l ed o r p r e d i c t a b l e s h o c kr a t h e r t h a n w i t h u n s i g n a l e d o r u n p r e d i c t a b l e s h o c k ; t h i s i st h e o p p o s i t e o f w h a t h a s b e e n r e p o r t e d i n o t h e r a n i m a l m o d -e l s o f p s y c h o s o m a t i c d i s e a s e . W e b e l i e v e th e d i f f e r e n c em i g h t r e l a te t o t h e t im e c o u r s e a n d t y p e o f p s y c h o s o m a t i cd i s e a s e u n d e r s t u d y . I n t h i s e x p e r i m e n t , v e n t r i c u l a r a u to -m a t i c i t y i n c r e a s e s o v e r a r a t h e r s h o r t t i m e f r a m e d u e t o i n-f u s i o n o f d ig i t a l is . S u p e r i m p o s e d o n t h i s a r e b r i e f p e r i o d s o fi n t e n s e b e h a v i o r a l d i s r u p t i o n ( i . e . , s t r e s s ) a n d v i s c e r a la r o u s a l p r o d u c e d b y t h e s i g n a l f o r s h o c k . I n n o r m a l a n i m a l sw i t h n o p r e d i s p o s i t i o n t o d i s e a s e , t h i s b r i e f s ti m u l u s i s i n -a d e q u a t e t o p r o d u c e d i s e a s e . I n s t e a d , u n s i g n a l e d s h o c kw h i c h p r o d u c e s a l e v e l o f m o d e r a t e b e h a v i o r a l d i s r u p t io n

t h r o u g h o u t a s t r e s s s e s s io n p r o d u c e s m o r e p a t h o l o g y , e s p e -c i a l l y s i n c e t h e s e s t r e s s s e s s i o n s a r e m a n y h o u r s l o n g . T h i si n t e r p r e t a t i o n i s r e i n f o r c e d b y a r e c e n t s t u d y i n w h i c h r a t st r e a t e d s i g n a l e d s h o c k a s m o r e a v e r s i v e t h a n u n s i g n a l e ds h o c k o f t h e s a m e i n t e n s i t y [ 8 0] .

p a t i e n t s t a k i n g d i g i t a l i s . T h e s e p e o p l e a r e s u s c e p t i b l e t o a r -r h y t h m i a s d u e t o t h e i r u n d e r l y i n g d i s e a s e a n d d u e t o t h e f a ctt h a t t h e y a r e t a k i n g d i g i t a li s , a d r u g w h i c h i t s e l f i s a r-r h y t h m o g e n i c . T h e i n f e r e n c e w e w o u l d d r a w i s t h a t in c o n -t r a s t t o o u r a n i m a l s w i t h h e a r t s f r e e o f d i s e a s e , p a t i e n t s t a k -i n g d i g i t a li s w h o h a v e h e a r t d i s e a s e a r e a t i n c r e a s e d r i s k tod e v e l o p a r r h y t h m i a s . T h i s l i n e o f r e a s o n i n g i s s u p p o r t e d b y ar e c e n t e p i d e m i o l o g i c a l s t u d y [ 8 2 ] s h o w i n g t h a t d i g i t a l i s i t s e l fa c t s a s a r i s k f a c t o r f o r s u d d e n d e a t h ; a l s o , i t i s k n o w n f r o me x p e r i m e n t a l w o r k t h a t t h e h e a r t i s m o r e l i k e l y t o d i s p l a ya r r h y t h m i a s a t a f i x e d d o s e o f t h e d r u g s h o r t l y a f te r a n a c u t ec a r d i a c i s c h e m i c e p i s o d e [ 6 8 ]. B e c a u s e d i g i t a l i s - t o x i c a r -r h y t h m i a s b e g i n e a r l i e r i n o t h e r w i s e n o r m a l g u i n e a p i g su n d e r p s y c h o l o g i c a l s t r e s s , w e b e l i e v e s t r e s s m i g h t b e e v e nm o r e o f a p r o b l e m i n d i g it a l iz e d p a ti e n t s w i t h c a r d i a c d i s-e a s e . C u r r e n t l y , w e a r e e v a l u a t i n g t h i s p o s s i b i l i t y i n a p a t i e n tp o p u l a t i o n t a k i n g d i g i t a l i s . R e g a r d l e s s , t h e d a t a f r o m t h i se x p e r i m e n t i n d i c a t e t h a t e m o t i o n a l f a c t o rs m u s t b e a d d e d t ot h e l i s t o f p o s s i b i l i t i e s t h e p h y s i c i a n c o n s i d e r s u p o n c o n f r o n t -i n g a p a t i e n t w i t h d i g i t a l i s t o x i c i t y .I n d i s c u s s i n g th i s s t u d y , a p o i n t s h o u l d b e m a d e a b o u t t h er e l a ti v e i m p o r t a n c e o f p s y c h o l o g i c a l a n d p h y s i c a l s t im u l i.T h e m a j o r w a y t h a t d i s c r im i n a t i o n s b e t w e e n t h e s e v a r i a b l e sh a s b e e n m a d e i s b y d o i n g s u i t a b l e c o n t r o l s in w h i c h t h en o c i c e p t i v e p h y s i c a l s t i m u l u s i s h e l d c o n s t a n t w h i l e t h e p s y -c h o l o g i c a l c o n t i n g e n c i e s a b o u t i t a r e v a r i e d ( e . g . , [ 7 9 ,1 2 8 ]) .I n t he a b o v e e

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