Basic Res. Cardiol. 72, 421-435 (1977) 9 1977 Dr. Dietrich Steinkopff Veriag, Darmstadt ISSN030(~8428

Sektion Kardiologie und Angiologie des Zentrums ]iir Innere Medizin und Kinderheilkunde, Abteilung Medizinische Statistik, Dokumentation und Datenverarbeitung der Universit~it Ulm

Electrocardiographic changes in cardiomyopathie Syrian hamsters (strain BIO 8262)*) Elektrokardiographisehe Veriinderungen bei syrisehen Goldhamstern mit Kardiomyopathie K. L o s s n i t z e r ,

N. G r e w e ,

A. K o n r a d ,

a n d J. A d l e r

With 2 figures and 6 tables (Received December 17, 1976) Summary Under ether anesthesia electrocardiograms were derived from Syrian h a m sters (strain BIO 8262) suffering from cardiomyopathy and muscular dystrophy. In addition, v e n t r i c u l a r weights and body weight were determined. Young hamsters - not yet showing morphological signs of the cardiomyopathy with the exception of possible left ventricular hypertrophy - demonstrated only a longer ventricular activation time than normal hamsters. With the onset of cardiac necrotization left axis deviation in frontal plane projection and right bundle branch blocks are developing in the cardiomyopathic hamsters followed by first degree atrioventricular conduction defects. During the late stage of the cardiomyopathy left b u n d l e branch blocks are additionally arising, while left ventricular hypertrophy is disappearing. Since no overt heart failure is occurring in this strain of cardiomyopathic hamsters, gradual development of high degree conduction defects is assumed to terminate their lives. The electrocardiographic pattern of the hamster cardiomyopathy fits partly into that of h u m a n p r i m a r y as well as secondary cardiomyopathy. Nevertheless, it seems to form an entity of its own, as arrhythmias, higher degree atrioventricular conduction disturbances, typical signs of ventricular or septal hypertrophy, abnormal P and Q waves, ST segment and T wave changes are lacking.

H u m a n c a r d i o m y o p a t h y is k n o w n to e x h i b i t c e r t a i n e l e c t r o c a r d i o graphic f e a t u r e s (2, 3, 4, 5, 7, 8, 11, 14, 19, 20, 22, 23, 25, 27, 28). It is of c l i n i cal interest w h e t h e r t h e s p o n t a n e o u s c a r d i o m y o p a t h y i n t h e S y r i a n hamsters is e l e c t r o c a r d i o g r a p h i c a l l y c o m p a r a b l e w i t h h u m a n c a r d i o m y o pathy. Moreover, it s e e m s of i m p o r t a n c e to d e s c r i b e d i s t i n c t stages of t h e disease b y a c l i n i c a l r o u t i n e m e t h o d , as m o r p h o l o g i c (21), b i o c h e m i c a l (16, 17, 18) a n d h e m o d y n a m i c (26) s t u d i e s h a v e a l r e a d y o u t l i n e d t h e course of the h a m s t e r c a r d i o m y o p a t h y . S i n c e n o t h i n g is k n o w n a b o u t t h e cause of death i n t h e d i s e a s e d a n i m a l s , t h e q u e s t i o n c o n c e r n i n g e l e c t r i c a l p r o blems in t h e i r h e a r t s s h o u l d be clarified. *) Mit Unterstfitzung der Deutschen Forschungsgemeinschaft

422

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Materials and m e t h o d s a.. A n i m a l s T h e e x p e r i m e n t s w e r e p e r f o r m e d on h a m s t e r s of b o t h s e x e s of the cardiom y o p a t h i c s t r a i n BIO 8262, w h i c h w a s d e v e l o p e d t h r o u g h cross-breeding b e t w e e n f e m a l e s of t h e o r i g i n a l m y o p a t h i c BIO 14.6 line a n d h e a l t h y males of t h e B I O R B line (see 16). T h e a n i m a l s are a f f l i c t e d w i t h a r e c e s s i v e autosomally t r a n s m i t t e d d i s o r d e r of t h e s t r i a t e d m u s c u l a t u r e a n d t h e myocardium. It is d e s c r i b e d as m u s c u l a r d y s t r o p h y a n d c a r d i o m y o p a t h y (1, 13, 21). According to t h e c l a s s i f i c a t i o n in h u m a n s (6, 10, 15, 24) t h e c a r d i o m y o p a t h y of the hamsters c a n b e l a b e l l e d as a s e c o n d a r y one. L i g h t m i c r o s c o p i c a n d histochemieal e x a m i n a t i o n s of t h e h e a r t s r e v e a l e d m u l t i f o c a l c o a g u l a t i o n n e c r o s e s predomi n a n t l y o c c u r i n g in t h e left v e n t r i c u l a r w a l l a n d s e p t u m (21). H e a l t h y animals f r o m a c o m m e r c i a l l y a v a i l a b l e s t r a i n s e r v e d as controls. All h a m s t e r s were kept u n d e r i d e n t i c a l c o n t r o l l e d h o u s i n g c o n d i t i o n s ; n o r m a l l a b o r a t o r y diet (SsniffH - h a m s t e r chow) a n d t a p w a t e r w e r e o f f e r e d a d l i b i t u m . b. E x p e r i m e n t s In accordance three age groups

with histopathological were established:

I. 29 to 32 days: II. 64 to 86 days: III. 231 to 280 days:

findings

in the BIO

8262 hamsters (21),

no myocardial lesions progressive multifocal coagulation necroses, calcification mainly of myocardial giant cells reduction of the number of new lesions, scar formation with calcification.

Fig. 1. C h e s t X - r a y of a 2 5 6 - d a y - o l d c a r d i o m y o p a t h i c f e m a l e hamster. Int0 p o i n t 1 ( s t e r n a l l i n e 5th i n t e r c o s t a l space, a b o u t e n d of s t e r n u m ) , point 2 (midc l a v i c u l a r line 4th i n t e r c o s t a l space), p o i n t 3 ( m i d a x i l l a r y line 4th intercostal space) e l e c t r o d e n e e d l e s w e r e p l a c e d s u b c u t a n e o u s l y f o r electrocardiograpNc t r a c i n g . T h e s e p o i n t s a r e d e m o n s t r a t e d in t h e i r r e l a t i o n to t h e h a m s t e r heart.

Lossnitzer et al., E l e c t r o c a r d i o g r a p h i c changes in c a r d i o m y o p a t h i c h a m s t e r s

423

Prior to t h e e l e c t r o c a r d i o g r a p h i c t r a c i n g t h e h a m s t e r s w e r e a n e s t h e t i z e d with e t h e r a n d f i x e d on a b o a r d in s u p i n e position, t h e i r e x t r e m i t i e s e x t e n d e d by r u b b e r b a n d s to t h e f o u r c o r n e r s . N e e d l e e l e c t r o d e s w e r e p l a c e d s u b cutaneously into t h e 4 e x t r e m i t i e s a n d on t h e t h o r a x . T h e b i p o l a r s t a n d a r d l e a d s I, II, III, a u g m e n t e d e x t r e m i t y l e a d s aVR, aVL, a V F a n d t h e u n i p o l a r p r e c o r d i a l leads d e r i v e d f r o m t h e 4th resp. 5th i n t e r c o s t a l s p a c e in t h e s t e r n a l , m i d c l a v i c ular and m i d a x i l l a r y line (fig. 1) w e r e r e g i s t r a t e d . A n a t o m i c a l s t u d i e s s h o w e d the lead f r o m t h e s t e r n a l line l y i n g o v e r t h e r i g h t a n d t h e l e a d s f r o m t h e midclavicular a n d m i d a x i l l a r y line lying o v e r t h e left v e n t r i c u l a r wall, t h e position of t h e v e n t r i c u l a r s e p t u m b e i n g s i m i l a r to t h a t in h u m a n h e a r t s . By repeatedly p u t t i n g t h e e l e c t r o d e s on t h e a n i m a l s i d e n t i c a l e l e c t r o c a r d i o g r a p h i c patterns c o u l d b e seen. For d o c u m e n t a t i o n t h e S i e m e n s M i n g o g r a p h 81 (6 c h a n n e l j e t ink w r i t e r ) was used. T h e p a p e r s p e e d w a s 250 m m / s e c . D u r i n g t h e p r o c e d u r e t h e Ecg w a s monitored on a n oscilloscope. It w a s o n l y r e g i s t r a t e d , w h e n t h e h e a r t r a t e h a d stabilized j u s t b e f o r e t h e a n i m a l s r e t u r n e d into t h e e x c i t a t i o n a l stage. After t h e e l e c t r o c a r d i o g r a p h i c t r a c i n g t h e h a m s t e r s w e r e sacrificed, w e i g h e d , and their h e a r t s excised. T h e a t r i a w e r e c a r e f u l l y r e m o v e d f r o m t h e v e n t r i c l e s . Thereafter t h e r i g h t v e n t r i c u l a r w a l l w a s e x a c t l y cut off f r o m t h e s e p t u m . The total v e n t r i c u l a r m y o c a r d i u m w a s t h e n g e n t l y b l o t t e d on a g a u z e p a d a n d weighed on a d i g i t a l m i c r o b a l a n c e ( S a r t o r i u s 2462). A f t e r r e m o v a l of t h e r i g h t ventricular m y o c a r d i u m f r o m t h e b a l a n c e t h e r e m a i n i n g left v e n t r i c u l a r t i s s u e with s e p t u m w a s r e w e i g h e d .

c. Statistical e v a l u a t i o n From e a c h of t h e p a r a m e t e r s m e a s u r e d t h e m e a n value, a d d i t i o n a l l y in healthy c o n t r o l h a m s t e r s w i t h a 5 % p r o b a b i l i t y of e r r o r t h e c o n f i d e n c e limits of the m e a n v a l u e s w e r e c a l c u l a t e d . W h e n t h e m e a n v a l u e of a p a r a m e t e r of the c a r d i o m y o p a t h i c a n i m a l s lay b e y o n d t h e c o n f i d e n c e l i m i t s a n o t h e r p o p u l a t i o n was postulated. T h e v a r i a b l e s w e r e p r e s u m e d to be n o r m a l l y d i s t r i b u t e d .

Results ~. G e n e r a l f i n d i n g s The m o s t s t r i k i n g f i n d i n g w a s s i n u s r h y t h m e x i s t i n g i n all a n i m a l s examined. P r e m a t u r e beats could not be observed. Atrioventricular conduction d e f e c t s o f s e c o n d o r t h i r d d e g r e e u s u a l l y d i d n o t o c c u r e x c e p t when e t h e r n a r c o s i s w a s t o o s t r o n g . T h i s f i n d i n g w a s a l s o r e p o r t e d b y Hoenig a n d M o h r (12), w h o w e r e t h e f i r s t t o d e r i v e e l e c t r o c a r d i o g r a m s from h a m s t e r s i n 1953. A t r i o v e n t r i c u l a r b l o c k s i n d u c e d b y e t h e r q u i c k l y disappeared w i t h d e c r e a s e of d e p t h of narcosis. In f i g u r e 2a a n d b t y p i c a l e l e c t r o c a r d i o g r a m s d e r i v e d f r o m a n o r m a l a n d a c a r d i o m y o p a t h i c h a m s t e r a r e d e m o n s t r a t e d . C o m p a r e d to n o r m a l h u m a n

electrocardiograms in all hamster electrocardiograms a lower voltage could be observed. No difference existed between normal and cardiomyopathic hamsters in this respect. The presence of deep abnormal Q waves as observed in diffuse myocardial diseases and hypertrophic cardiomyopathies in humans could not be evidenced in the cardiomyopathic hamsters. Abnormalities of the ST segments and T waves were scarce, 0nly very slight, and without any relation to the cardiomyopathy. The ST segments most frequently were isoelectric and the T waves of little height, the transition between both being fluent. Sometimes the T waves were

Basic Research i~ Cardiology, Vol. 72, No. 4 (1977~

424

~ ' ~

I

'~'

.-

t

~'-

_r

oVL MIDAXILLARY LINE

oVF I

m

Fig. 2. a. Electrocardiogram of a 262-day-old male control hamster. The tracings are copied with black ink on t r a n s l u c e n t parchment paper for better contrast. Paper speed 250 mm/sec. The voltage is relatively low in comparison to human electrocardiograms. P and T waves are flat in the limb leads and in the midaxillary line of the chest. They can be better discerned in sternal and midclavicular line. However, as it can be seen there the T waves are superimposed in their terminal parts by succeeding P waves. s t r a i g h t e n e d , a n i n v e r s i o n could n e v e r be seen. C h a n g e s of t h e ST segment - if e v e r o c c u r r i n g - consisted of ascension. I n a d d i t i o n , the end of the T w a v e s c o u l d h a r d l y b e d e f i n e d , as t h e y m o s t l y w e r e superimposed in t h e i r t e r m i n a l p a r t s b y s u c c e e d i n g P w a v e s (fig. 2a a n d b). Hence, e v a l u a t i o n of t h e QT t i m e w a s impossible.

b. S p e c i i i c ]indings I n t a b l e 1 t h e b e h a v i o u r of t h e d i r e c t i o n of t h e e l e c t r i c a l heart axis w i t h age i n f r o n t a l p l a n e p r o j e c t i o n is d e m o n s t r a t e d . I n y o u n g hamsters of t h e f i r s t age g r o u p t h e e l e c t r i c a l h e a r t axis e x h i b i t s a n intermediate p o s i t i o n b e t w e e n 4- 30 ~ a n d 4- 60 ~ i n m o s t of t h e a n i m a l s without d i f f e r e n c e b e t w e e n h e a l t h y a n d c a r d i o m y o p a t h i c . W i t h i n c r e a s i n g age it shifts to t h e left side u n t i l ~ - 3 0 ~ i n m a n y of t h e cardiomyopathic h a m s t e r s , w h e r e a s t h e r e is a n opposite d e f l e c t i o n to v e r t i c a l position ( ~ 4 - 6 0 ~ ~ + 110 ~ i n m o s t of t h e c o n t r o l a n i m a l s w i t h no further d e v i a t i o n i n the oldest c o n t r o l a n i m a l s e x a m i n e d . T h e b e h a v i o u r of t h e h e i g h t of t h e R w a v e s i n t h e chest leads cannot be u s e d to e s t i m a t e t h e d i r e c t i o n of t h e e l e c t r i c a l h e a r t v e c t o r i n horizontal p l a n e p r o j e c t i o n , as t h e a m p l i t u d e of t h e QRS c o m p l e x e s varies with r e s i s t a n c e d e p e n d i n g o n t h e d e p t h of t h e e l e c t r o d e n e e d l e s placed subc u t a n e o u s l y . F o r a coarse e s t i m a t i o n of t h e d o r s a l deflection of the e l e c t r i c a l h e a r t axis the R/S r e l a t i o n i n t h e s t e r n a l lead w a s t a k e n (table 2). W h e r e a s i n t h e f i r s t t w o age g r o u p s t h e r e exists n o d i f f e r e n c e in R/S rel a t i o n b e t w e e n c o n t r o l a n d c a r d i o m y o p a t h i c h a m s t e r s , i n the third age

Lossnitzer et al., Electrocardiographic changes in cardiomyopathic hamsters

425

I

STERNAL LINE

:LI

V

-

MIDCLAVICULAR LINE

aVR

aVL i

o V IF~

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,

b. Electrocardiogram of a 257-day-old cardiomyopathic male hamster. The tracings are in the same m a n n e r copied from the original as those of the control hamster. Again low voltage as in the control animal. P and T waves are flat in the limb leads; P waves a r e a little more pronounced in the chest leads. T waves are again superimposed by succeeding P waves. Hence, QT time cannot be exactly determined. In contrast to the electrocardiogram of the control hamster there are deep S waves in leads II, I I I and aVF, the R/S relation in sternal line is much lower, the QRS interval is w i d e r and a notch can be detected in the ascending limb of R in the tracing derived from the midclavicular and m i d a x i l l a r y line. These changes will t u r n out as being among the features of the hamster cardiomyopathy. group t h e n u m b e r of t h e c a r d i o m y o p a t h i c a n i m a l s w i t h R / S r e l a t i o n less than 0 . 5 - e v e n less t h a n 0 . 2 - e x c e e d s u n d o u b t e d l y t h a t of t h e c o n t r o l group. In o r d e r to c l a r i f y t h e q u e s t i o n w h e t h e r t h e l e f t a n d d o r s a l d e f l e c t i o n of the e l e c t r i c a l m a i n v e c t o r of t h e o l d e r c a r d i o m y o p a t h i c h a m s t e r s is caused b y l e f t h e a r t h y p e r t r o p h y h e a r t w e i g h t , l e f t a n d r i g h t v e n t r i c u l a r weights, r e l a t i o n of l e f t / r i g h t v e n t r i c u l a r w e i g h t , h e a r t i n d e x a n d b o d y weight w e r e d e t e r m i n e d ( t a b l e 3). I n t h e f i r s t a g e g r o u p s i m i l a r h e a r t weight a n d l e f t v e n t r i c u l a r w e i g h t does exist, h o w e v e r , l o w e r r i g h t ventricular w e i g h t a n d i n c r e a s e d r e l a t i o n of l e f t / r i g h t v e n t r i c u l a r w e i g h t is obvious in 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 s . T o g e t h e r w i t h l o w e r b o d y weight a n d i n c r e a s e d h e a r t i n d e x t h e s e f i n d i n g s p o i n t to r e l a t i v e l y increased l e f t v e n t r i c u l a r w e i g h t in 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 s in comparison to t h e c o n t r o l s . I n t h e s e c o n d age g r o u p h e a r t w e i g h t , l e f t ventricular w e i g h t a n d l e f t / r i g h t v e n t r i c u l a r w e i g h t r e l a t i o n a n d h e a r t index a r e i n c r e a s e d in t h e c a r d i o m y o p a t h i c a n i m a l s , r i g h t v e n t r i c u l a r weight a n d b o d y w e i g h t s h o w i n g no d i f f e r e n c e b e t w e e n c a r d i o m y o p a t h i c and h e a l t h y . A s b o d y w e i g h t of b o t h h a m s t e r s t r a i n s is s i m i l a r i n c r e a s e d left v e n t r i c u l a r w e i g h t h a s n o w b e e n p r o v e n d i r e c t l y . I n t h e o l d e s t a g e group o n l y i n c r e a s e d h e a r t i n d e x is o b v i o u s i n t h e c a r d i o m y o p a t h i c hamsters, c e r t a i n l y as a c a l c u l a t i v e c o n s e q u e n c e of i n s i g n i f i c a n t l y d e -

426

Basic Research in Cardiology, Vol. 72, No. 4 (1977)

§ A

Q

r

+ V

~9

+ A

0 9

~4

9

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9

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I

Lossnitzer et al., Electrocardiographic changes in cardiomyopathic hamsters

427

Table 2. R/S relation in sternal chest lead in normal and eardiomyopathic hamstcrs of different ages. Age (days)

Strain

R/S < 0.5

R/S < 0.2

]3IO 8262

3

1

Controls

0

0

BIO 8262

2

1

Controls

2

0

BIO 8262

14

10

Controls

4

1

29-32

64-86

231-280

The figures represent the number of animals of a total of 26 in each group (BIO 8262; Controls). creased b o d y a n d i n c r e a s e d h e a r t w e i g h t . S i n c e l e f t v e n t r i c u l a r a n d b o d y weight as w e l l as t h e r e l a t i o n of l e f t / r i g h t v e n t r i c u l a r w e i g h t do n o t d i f f e r from t h e c o n t r o l s e l e v a t e d l e f t v e n t r i c u l a r w e i g h t in old c a r d i o m y o p a t h i c hamsters c a n b e e x c l u d e d . The h e a r t r a t e of all t h r e e a g e g r o u p s ( t a b l e 4) e x h i b i t s no d i f f e r e n c e between c a r d i o m y o p a t h i c a n d c o n t r o l h a m s t e r s , h o w e v e r , a t e n d e n c y to decrease w i t h a g e in b o t h s t r a i n s of a n i m a l s c a n n o t b e d e n i e d . T h e r a n g e of the h e a r t r a t e s is in a c c o r d a n c e w i t h t h a t f o u n d in g o l d e n h a m s t e r s b y t{oenig a n d M o h r (12). In t a b l e 5 t h e PQ, Q R S i n t e r v a l a n d t h e v e n t r i c u l a r a c t i v a t i o n t i m e (VAT) in s t e r n a l a n d m i d a x i l l a r y l i n e a r e d e m o n s t r a t e d . I n t h e f i r s t age group o n l y t h e V A T in t h e m i d a x i l l a r y l i n e is o b v i o u s l y d e l a y e d in h e a r t s of the c a r d i o m y o p a t h i c h a m s t e r s . I n t h e s e c o n d a g e g r o u p P Q i n t e r v a l is longer a n d V A T - b o t h in s t e r n a l as w e l l as m i d a x i l l a r y l i n e - a r e also longer in 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 s t h a n in t h e controls, a l t h o u g h t h e QRS i n t e r v a l is n o t w i d e n e d . 9 resp. 4 o u t of 26 c a r d i o m y o p a t h i c h a m s t e r s show a t y p i c a l M - s p l i t t e d ( s t e r n a l line) r i g h t (RBBB), resp. n o t c h e d l e f t (midaxillary line) b u n d l e b r a n c h b l o c k (LBBB) Q R S c o m p l e x (fig. 2b), whereas o n l y 5 resp. 2 o u t of 26 c o n t r o l h a m s t e r s ( t a b l e 6). I n t h e t h i r d again as in t h e f i r s t a g e g r o u p V A T is o n l y d e l a y e d in t h e m i d a x i l l a r y line of c a r d i o m y o p a t h i c h a m s t e r s . B u t now, in c o n t r a s t to t h e f i r s t a g e group t h e Q R S i n t e r v a l is u n d o u b t e d l y w i d e r in c a r d i o m y o p a t h i c h e a r t s (table 5). 10 o u t of 26 c a r d i o m y o p a t h i c h a m s t e r s e x h i b i t t h e t y p i c a l L B B B pattern w h e r e a s o n l y 1 o u t of 26 c o n t r o l h a m s t e r s ( t a b l e 6). T h e c h a r a c t e r istic RBBB p a t t e r n c a n b e s e e n in 12 resp. 8 o u t of 26 c a r d i o m y o p a t h i c , resp. c o n t r o l h a m s t e r s . I n all a n i m a l s w i t h R B B B o r L B B B p a t t e r n V A T is equal to o r l o n g e r t h a n 10 msec. a n d t h e Q R S i n t e r v a l lies b e t w e e n 20 and 28 msec.

428

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Table 4. Heart rate of normal and cardiomyopathic hamsters of different ages. Age (days)

Heart rate (min -1) BIO 8262 Controls

29-32 64-86 231-280

445 441 422

440 ~ 60 429 i 48 411 =t= 22

The figures represent mean values; additionally in the control groups the confidence limits of the mean values (5% probability). 26 hamsters in each group. The PQ i n t e r v a l of c a r d i o m y o p a t h i c a n i m a l s of the t h i r d age g r o u p is again w i d e r t h a n t h a t of the controls (table 5). While in the second age group only 3 c a r d i o m y o p a t h i c h a m s t e r s d i s p l a y a PQ i n t e r v a l equal to or longer t h a n 52 msec. (1 ~ AV block), t h e r e a r e 14 in the t h i r d age g r o u p which do so. O n l y 1 control h a m s t e r of the second and 2 of the t h i r d age group do fulfill these c r i t e r i a (table 6). C o m b i n a t i o n of RBBB w i t h 1 ~ AV block can be seen in 7 c a r d i o m y o p a t h i c h a m s t e r s of the t h i r d age group, while c o m b i n a t i o n of LBBB w i t h 1 ~ AV block does occur o n l y in 2 cardiomyopathic a n i m a l s (table 6). These possibly b i l a t e r a l b u n d l e branch blocks c a n n o t be d e t e c t e d in the control hamsters. Combined RBBB and LBBB b e c a m e obvious in 3 c a r d i o m y o p a t h i c a n i m a l s of the second as well as of the t h i r d age group, a n d the c o m b i n a t i o n of 1 ~ AV block (PQ interval 60 resp. 56 msec.) w i t h RBBB and LBBB in 1 c a r d i o m y o p a t h i c hamster of the same age g r o u p s (table 6). None of the control h a m s t e r s does reveal these high d e g r e e conduction defects. Discussion Until the sixth w e e k of life the h e a r t s of the c a r d i o m y o p a t h i c h a m s t e r s appear light m i c r o s c o p i c a l l y n o r m a l , while m u s c u l a r d y s t r o p h y is a l r e a d y present since b i r t h (21). In 29 to 32 d a y old c a r d i o m y o p a t h i c h a m s t e r s relatively i n c r e a s e d left v e n t r i c u l a r w e i g h t of the p r e n e c r o t i c h e a r t s can be seen. However, e l e c t r o c a r d i o g r a p h i c a l l y left v e n t r i c u l a r h y p e r t r o p h y cannot be detected u n e q u i v o c a l l y . O n l y V A T in m i d a x i l l a r y line is l o n g e r indicating a slight left v e n t r i c u l a r conduction delay. Hence, left h e a r t hypertrophy of m i n o r d e g r e e m i g h t exist, as the w e i g h t studies a n d the delay of conduction p o i n t to this possibility. During the n e c r o t i z i n g stage of the c a r d i o m y o p a t h y (64 to 86 d a y old hamsters) h e a r t axis d e v i a t i o n to the left side in f r o n t a l p l a n e p r o j e c t i o n becomes e l e c t r o c a r d i o g r a p h i c a l l y a p p a r e n t , w h e r e a s in n o r m a l h a m s t e r s the heart axis shifts to v e r t i c a l position. D i f f e r e n t d e v i a t i o n of e l e c t r i c a l heart axis in h o r i z o n t a l p l a n e p r o j e c t i o n cannot be e v i d e n c e d b e t w e e n cardiomyopathic and control animals, when looking at the R/S relation. VAT in m i d a x i l l a r y as well as s t e r n a l line is delayed, however, the QRS interval again not being widened. As in this stage of the disease no significant d i f f e r e n c e of LBBB p a t t e r n s does exist b e t w e e n c a r d i o m y o p a t h i c and control h a m s t e r s (table 6), d e l a y e d V A T in m i d a x i l l a r y line m i g h t be in accordance w i t h left v e n t r i c u l a r h y p e r t r o p h y . W e i g h t a n a l y s e s do now

430

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clearly demonstrate increase of left ventricular weight in the cardiomy0pathic hamsters. The delay of VAT in sternal line, however, cannot be attributed to right heart hypertrophy, as none of the measured weight parameters does agree with this possibility. Hence, 9 cardiomyopathic hamsters with RBBB pattern in comparison with 5 control hamsters showing this a b n o r m a l i t y seem to demonstrate predominantly right ventricular conduction defect provoked by the cardiomyopathy. Additionally, slightly prolonged PQ intervals also display the onset of atrioventricular conduction defects during the course of the heart disease. In old cardiomyopathic hamsters distinctly increased right or left ventricular weights could be excluded. However, an increased number of animals exhibited heart axis deviation to the left side in frontal and now additionally in horizontal plane projection. QRS interval and VAT in midaxillary line are prolonged. Since 10 out of 26 cardiomyopathic hamsters display a typical LBBB pattern in their electrocardiograms (see fig. 2b and table 6) occurrence of left ventricular conduction defects during this ]ate stage of the c a r d i o m y o p a t h y must be assumed, while left ventricular h y p e r t r o p h y is disappearing. However, extensive dilation of the left heart chamber does not seem to take place, since h e m o d y n a m i c studies did not reveal elevated left ventricular enddiastolic pressure (26). Interestingly, VAT in sternal line now does not more differ from control hamsters. A possible explanation might be the increased incidence of unspecific RBBB in the control animals (table 6). Therefore, it becomes apparent that during the course of the c a r d i o m y o p a t h y RBBB are occurring prior to LBBB. Although, already during the second stage of the cardiomy0p a t h y the PQ interval is prolonged (table 5), distinct first degree atri0ventricular conduction defects mostly emerge in old cardiomyopathic animals (table 6). From all these findings it can be concluded that during the prenecr0tic stage of the c a r d i o m y o p a t h y there exists possibly slight left ventricular hypertrophy, which is regressive with increasing age, whereas right and left ventricular as well as atrioventricular conduction disturbances are successively arising. Hence, not only ventricular working myocardium, but also the conduction system gets affected by the inherited degenerative heart disease. However, the atrioventricular conduction system as well as the sinus node do not seem to get largely involved in the disease process, as heart rate is similar in cardiomyopathic and control hamsters (table 4} and atrioventricular conduction disorders of second or third degree as well as a r r h y t h m i a s cannot be observed. Since overt heart failure does not develop in the cardiomyopathic hamsters of strain BIO 8262 (26), electrical conduction defects of their hearts might keep them from longevity. The gradual occurrence of possibly bilateral blocks (table 6) might cease the life of the cardiomyopathic hamsters. Nevertheless, one has to be cautious with this reasoning, since nothing is k n o w n about the diagnostic as well as prognostic significance of the pathological electrocardiographic changes in hamsters. Histochemical fluorescence microscopical investigations on the conduction system of various mammals (golden hamsters, mice and rats) revealed differences in metabolism and innervation (9). The lifespan of the cardi0-

Lossnitzer et al., Electrocardiographic changes in cardiomyopathic hamsters

433

myopathic h a m s t e r s is a b o u t 200 to 400 days; n o r m a l h a m s t e r s are r e p o r t e d to live f o r t w o to t h r e e years. This fact, h o w e v e r , could s u p p o r t the a b o v e made assumption. Now, the q u e s t i o n s h o u l d be discussed, w h e t h e r the s p o n t a n e o u s hamster c a r d i o m y o p a t h y resembles e l e c t r o c a r d i o g r a p h i c a l l y h u m a n c a r diomyopathy. As the h a m s t e r c a r d i o m y o p a t h y is c o m b i n e d w i t h muscular d y s t r o p h y e l e c t r o c a r d i o g r a p h i c a l findings o c c u r r i n g in h u m a n s suffering f r o m m u s c u l a r d y s t r o p h y a n d of the h a m s t e r s shall be compared. A r r h y t h m i a s , 2 : 1 a t r i o v e n t r i c u l a r block or changes of the heart rate could n o t be o b s e r v e d in the hamsters, as it is r e p o r t e d in progressive m u s c u l a r d y s t r o p h y in m a n (4, 14, 22, 27, 28). Also tall right p r e c o r d i a l R w a v e s a n d deep Q w a v e s in the limb leads a n d over the left p r e c o r d i u m , t a k e n as distinctive e l e c t r o c a r d i o g r a p h i c p a t t e r n in Duchenne's p r o g r e s s i v e m u s c u l a r d y s t r o p h y (22) w e r e n e v e r seen. However, i n t r a v e n t r i c u l a r c o n d u c t i o n defects as r e p o r t e d b y B e c k m a n n and S c h m i t (4) in D u c h e n n e ' s as well as limb girdle m u s c u l a r d y s t r o p h y , could be also discovered in the d y s t r o p h i c c a r d i o m y o p a t h i c hamsters. T h e predominant e l e c t r o c a r d i o g r a p h i c findings in the c a r d i o m y o p a t h i c h a m sters, as t h e r e are left a n d dorsal electrical h e a r t axis deviations, P Q prolongation and i n t r a v e n t r i c u l a r c o n d u c t i o n defects are also f e a t u r e s in patients w i t h p r i m a r y c a r d i o m y o p a t h y w i t h a n d w i t h o u t h y p e r t r o p h y {2, 7, 11, 19, 20, 25) and in patients w i t h alcoholic c a r d i o m y o p a t h y (3). Arrhythmias, as t a c h y c a r d i a , atrial fibrillation and v e n t r i c u l a r p r e m a t u r e beats, changes of P waves, p r e e x c i t a t i o n s y n d r o m e , deep Q waves, signs of left heart h y p e r t r o p h y , S T s e g m e n t and T w a v e abnormalities, often seen in patients w i t h p r i m a r y and alcoholic c a r d i o m y o p a t h y (2, 7, 11, 19, 20, 23, 27 and 3), as well as the last t h r e e signs also noticed in F r i e d r e i c h ' s disease (8), could n e v e r be e v i d e n c e d in the c a r d i o m y o p a t h i c hamsters. Nevertheless, it can be c o n c l u d e d t h a t the e l e c t r o c a r d i o g r a p h i c p a t t e r n of the h a m s t e r c a r d i o m y o p a t h y fits p a r t l y into t h a t of h u m a n p r i m a r y as well as s e c o n d a r y c a r d i o m y o p a t h y . H o w e v e r , it m u s t be also stated t h a t there do not exist h i g h l y specific and h e n c e diagnostic e l e c t r o c a r d i o g r a p h i c patterns in a n y f o r m of h u m a n c a r d i o m y o p a t h y . The h a m s t e r c a r d i o m y o pathy itself seems to be m o r e or less exceptional, since a r r h y t h m i a s , higher d e g r e e a t r i o v e n t r i c u l a r c o n d u c t i o n disturbances, typical signs of ventricular of septal h y p e r t r o p h y , a b n o r m a l Q waves, P w a v e as well as ST segment and T w a v e c h a n g e s are missing in their e l e c t r o c a r d i o g r a m s . Zusammenfassung

In .~thernarkose wurden bei syrischen Goldhamstern (Stamm BIO 8262), die an einer Kardiomyopathie und Skelettmuskeldystrophie leiden, Elektrokardiogramme abgeleitet. Zustitzlich wurden die links- und rechtsventrikultiren Gewichte der Herzen und das KSrpergewicht dieser Tiere bestimmt. Junge Tiere, die mit Ausnahme einer fraglichen Linksherzhypertrophie noch keine morpho10gischen Zeichen der Kardiomyopathie aufweisen, zeigen lediglich eine l~ingere Dauer bis zum Beginn der gr0f~ten Negativit~tsbewegung. Mit dem Auftreten v0n Herznekrosen setzen eine Abweichung der elektrischen Herzachse in der Fmntalebene nach links ein sowie das Auftreten yon RechtsschenkelblScken, denen AV-Bl~cke 1. Grades folgen. Im Endstadium der Kardiomyopathie treten n0ch zus~tzlich Linksschenkelbl5cke auf, w~hrend die Linkshypertrophie ver-

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s c h w i n d e t . D a sich bei d i e s e n T i e r e n k e i n e m a n i f e s t e H e r z i n s u f f i z i e n z entw i c k e l t , w i r d a n g e n o m m e n , dal~ die g r a d u e l l e E n t w i c k l u n g y o n bilateralen B16cken i h r L e b e n t e r m i n i e r t . Die e l e k t r o k a r d i o g r a p h i s c h e n Z e i c h e n d i e s e r H a m s t e r k a r d i o m y o p a t h i e pass e n t e i l w e i s e s o w o h l z u r p r i m ~ r e n w i e a u c h z u r s e k u n d ~ i r e n Kardiomyopathie d e s M e n s c h e n . D e n n o c h s c h e i n t diese i m T i e r r e i c h e v o r k o m m e n d e Kardiomy0p a t h i e in g e w i s s e m G r a d e eigenst~indig zu sein, d a A r r h y t h m i e n , hShergradige AV-B15cke, Z e i c h e n e i n e r V e n t r i k e l - o d e r S e p t u m h y p e r t r o p h i e , abnormale P - W e l l e n u n d Q - Z a c k e n s o w i e E n d s t r e c k e n v e r ~ n d e r u n g e n n i c h t beobachtet werden konnten.

Re~ferences i. Bajusz, E.: H e r e d i t a r y c a r d i o m y o p a t h y : a n e w d i s e a s e model. Amer. Heart J. 77, 686 (1969). 2. Banta, H. D., E. H. Estes: E l e c t r o c a r d i o g r a p h i c a n d vectorcardiographic f i n d i n g s i n p a t i e n t s w i t h i d i o p a t h i c m y o c a r d i a l h y p e r t r o p h y . A m e r . J. Cardi01. 14, 218 (1964). 3. Bashur, T. T., H. Fahdut, T. O. Cheng: E l e c t r o c a r d i o g r a p h i c abnormalities in a l c o h o l i c c a r d i o m y o p a t h y . C h e s t 68, 24 (1975). 4. B e c k m a n n , R., B. Schmit: D a s H e r z b e i M u s k e l e r k r a n k u n g e n . Tell 1: Musk e l d y s t r o p h i e n , b e s o n d e r s D u c h e n n e - M u s k e l d y s t r o p h i e . h/Ied. Klin. 71, 1135 (1976). 5. Davies, H., W. Evans: T h e s i g n i f i c a n c e of d e e p S w a v e s i n l e a d s II and III. B r i t . H e a r t J. 22, 551 (1960). 6. Fej:ar, Z.: C a r d i o m y o p a t h i e s - A n i n t e r n a t i o n a l p r o b l e m . Cardiologia 52, 9 (1968). 7. F r a n k , S., E. B r a u n w a l d : I d i o p a t h i c h y p e r t r o p h i c s u b a o r t i c stenosis. Clinical a n a l y s i s of 126 p a t i e n t s w i t h e m p h a s i s o n t h e n a t u r a l h i s t o r y . Circulation 37, 759 (1968). 8. Graham, G. R.: F r i e d r e i c h ' s disease. I n : W o l s t e n h o l m e a n d O'Connor, CIBA f o u n d a t i o n s t u d y g r o u p No. 37: H y p e r t r o p h i c o b s t r u c t i v e cardiomyopathy, pp. 358 ( L o n d o n 1971). 9. Gossrau, R.: H i s t o c h e m i s c h e , f l u o r e s z e n z m i k r o s k o p i s c h e u n d experimentelle U n t e r s u c h u n g e n a m R e i z l e i t u n g s s y s t e m y o n G o t d h a m s t e r , Nlaus und Ratte. H i s t o c h e m i e 26, 44 (1971). 10. Grosse-Brockhoff, F.: Z u r K l a s s i f i z i e r u n g , A t i o l o g i e u n d P a t h o g e n e s e der M y o k a r d i o p a t h i e n . Dtsch. Med. Wschr. 96, 659 (1971). 11. H a m b y , R. I., F. Raia: E l e c t r o c a r d i o g r a p h i c a s p e c t s of p r i m a r y myocardiaI d i s e a s e i n 60 p a t i e n t s . A m e r . H e a r t J. 76, 316 (1968). 12. Hoenig, W., W. Mohr: E l e k t r o k a r d i o g r a p h i s c h e S t u d i e n b e i m Goldhamster, e i n e m n e u e r d i n g s v i e l v e r w e n d e t e n L a b o r a t o r i u m s t i e r . Z. T r o p e n m e d . Parasit. 4, 117 (1953). 13. H o m b u r g e r , F., C. W. Nixon, M. Eppenberger, J. R. Baker: Hereditary m y o p a t h y i n S y r i a n h a m s t e r : s t u d i e s o n p a t h o g e n e s i s . A n n . N.Y. Acad. Sci. 138, 14 (1966). 14. James, T. N.: O b s e r v a t i o n s o n t h e c a r d i o v a s c u l a r i n v o l v e m e n t , including the c a r d i a c c o n d u c t i o n s y s t e m , i n p r o g r e s s i v e m u s c u l a r d y s t r o p h y . Amer. Heart J. 63, 48 (1962). 15. Kochsiek, K.: K l a s s i f i z i e r u n g d e r K a r d i o m y o p a t h i e n . Miinch. Med. Wschr. 118, 741 (1976). 16. Lossnitzer, K.: G e n e t i c i n d u c t i o n of a c a r d i o m y o p a t h y . I n : J. Schmier and O. Eichter, H a n d b o o k of E x p e r i m e n t a l P h a r m a c o l o g y , Vol. XVI/3, pp. 309 (Berlin, H e i d e l b e r g , N e w Y o r k 1975). 17. Lossnitzer, K., J. Janke, B. Hein, M. Stauch, A. Fleckenstein: Disturbed m y o c a r d i a l c a l c i u m m e t a b o l i s m - A p o s s i b l e p a t h o g e n e t i c f a c t o r in the hered-

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