Basic Res. Cardiol. 74, 435-444 (1979) 9 1979 Dr. Dietrich Steinkopff Verlag, Darmstadt ISSN 0300-8428
Insitut f~r Pathologie, Universit~t Z~rich (Direktoren: Prof. Chr. Hedinger/Prof. J. R. RiJttner)
M o r p h o l o g i c a l a l t e r a t i o n s of n o n - v a r i c o s e a n d varicose veins (A m o r p h o l o g i c a l c o n t r i b u t i o n to the d i s c u s s i o n on p a t h o g e n e s i s of v a r i c o s e veins)
M o r p h o l o g i s c h e Ver~inderungen in n i c h t v a r i k 6 s e n u n d in v a r i k 6 s e n V e n e n (Ein morphologischer Beitrag zur Diskussion Pathogenese der Varikosis)
H. J. Leu,
M. Vogt,
fiber die
and H. Pfrunder
With 5 figures and 5 tables (Received December 20, 1978)
Summary Venous valves do not play a role in pathogenesis of primary varicose veins. Their n u m b e r remains constant during life time. I n varicose veins their insufficiency is secondary. Intimal fibrosis is no prerequisite for the development of varicose veins. It is a frequent finding in non-varicose veins of all age groups. Fibrosis of media and adventitia is no early morphological alteration in varicose veins. Fibrotic replacement of smooth muscles represents a late stage of varicosis. Degenerative lesions of deep leg veins are rare even at old age. The deep veins are not influenced by sclerotic lesions of the adjacent arteries. Preexisting intimal fibrosis in autogenous graft veins may be one of several factors which induce an overshooting intimal proliferation. Degenerative alterations (fibrotic lesions of the wall layers, insufficiency of the valves) are secondary p h e n o m e n a in pathogenesis of varicose veins which follow a functional deficiency of the smooth musculature.
E t i o l o g y a n d p a t h o g e n e s i s of v a r i c o s i s a r e still o p e n to d i s c u s s i o n . I n t h e l a s t d e c a d e , e p i d e m i o l o g i c a l i n v e s t i g a t i o n s h a v e s h o w n t h a t a g i n g is t h e m a i n e t i o l o g i c a l f a c t o r w h e r e a s t h e i n f l u e n c e of sex, p r e g n a n c y , o b e s i t y a n d o c c u p a t i o n h a s b e e n o v e r r a t e d (15). A s far as p a t h o g e n e s i s is c o n c e r n e d , s o m e a u t h o r s (4, 10, 13) b e l i e v e t h a t a d e c r e a s e i n n u m b e r of v e n o u s v a l v e s is r e s p o n s i b l e for t h e d e v e l o p m e n t of v a r i c o s e v e i n s . O t h e r s c o n s i d e r d e g e n e r a t i v e w a l l l e s i o n s as t h e p r i m a r y f a c t o r (3, 7, 12, 14). As a m o r p h o l o g i c a l c o n t r i b u t i o n to this d i s c u s s i o n we h a v e investig a t e d s u p e r f i c i a l a n d d e e p v e i n s of t h e l o w e r e x t r e m i t i e s of a t o t a l of 178 s u b j e c t s w i t h o u t v e n o u s d i s o r d e r s a n d of 70 s u b j e c t s w i t h p r i m a r y varicose veins.
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Material and m e t h o d Our investigation included: 1. n u m b e r , l o c a l i z a t i o n a n d h i s t o l o g y of v e n o u s v a l v e s in t h e e x t e r n a l iliac a n d t h e p r o x i m a l s e g m e n t s of t h e f e m o r a l a n d l o n g s a p h e n o u s v e i n i n 70 s u b j e c t s of various age without venous disorders; 2. n u m b e r , l o c a l i z a t i o n a n d d e g r e e of d e g e n e r a t i v e wall l e s i o n s a) in t h e p r o x i m a l , m i d d l e a n d d i s t a l s e g m e n t s of t h e l o n g s a p h e n o u s v e i n of 52 s u b j e c t s of v a r i o u s a g e w i t h o u t v e n o u s d i s o r d e r s , b) in t h e s u p e r f i c i a l s a p h e n o u s b r a n c h e s of t h e l o w e r leg of 49 s u b j e c t s a b o v e t h e a g e of 40, c) i n t h e iliac a n d f e m o r a l v e i n of 30 s u b j e c t s , d) i n t h e d e e p l o w e r leg v e i n s of 47 l i m b s w h i c h h a d b e e n a m p u t a t e d d u e to arteriosclerotic gangrene; 3. t h e d e g r e e of d e g e n e r a t i v e wall l e s i o n s i n 70 v a r i c o s e veins. T h e m a t e r i a l of g r o u p 1 a n d 2a, b, c w a s o b t a i n e d a t a u t o p s y . C a s e s w i t h a n a m n e s t i c d a t a or m a c r o s c o p i c s i g n s of old or f r e s h v e n o u s d i s o r d e r s w e r e excluded. The veins were carefully removed and dissected. Number and distribut i o n of t h e v a l v e s w e r e n o t e d . H i s t o l o g y c o n s i s t e d of l i g h t m i c r o s c o p e e x a m i n a t i o n at v a r i o u s sites (stains: h e m a l a u n - e o s i n , v a n G i e s o n , e l a s t i n , o r c e i n a n d a l c i a n b l u e PAS). T h e m a t e r i a l of g r o u p 2 d w a s o b t a i n e d f r o m a m p u t a t e d l i m b s w i t h a r t e r i o sclerotic gangrene. The deep veins together with the deep lymph collectors were r e m o v e d a n d e x a m i n e d a t v a r i o u s sites. T h e m a t e r i a l of g r o u p 3 c o n s i s t e d of s u r g i c a l l y r e m o v e d v a r i c o s e v e i n s . 38 v e i n s w e r e v a r i c o s e l o n g s a p h e n o u s v e i n s a n d 32 w e r e p r i m a r y i n s u f f i c i e n t p e r f o r a t o r s s i t u a t e d at t h e m e d i a l d i s t a l r e g i o n of t h e l o w e r leg ( C o c k e t t p e r f o r a t o r s ) . (For s u p p l y of t h i s m a t e r i a l w e a r e i n d e p t e d to Prof. U. B r u n n e r , U n i v e r s i t y H o s p i t a l Zilrich, Dr. R. Fischer, R e g i o n a l H o s p i t a l W a t t w i l a n d Dr. W. MiHler, R e g i o n a l H o s p i t a l Brugg).
Results G r o u p 1: V e n o u s v a l v e s O f t h e 70 s u b j e c t s , 32 w e r e m e n a n d 38 w e r e w o m e n . 9 w e r e b e l o w t h e a g e o f 40, 23 w e r e b e t w e e n 40 a n d 60, a n d 38 w e r e b e t w e e n 61 a n d 90 y e a r s of age.
Fig. 1. N o n - v a r i c o s e s u p e r f i c i a l v e i n w i t h p r o m i n e n t i n t i m a l f i b r o s i s a n d s l i g h t f i b r o s i s of m e d i a a n d a d v e n t i t i a . V a n G i e s o n , 30•
L e u et al., Morphological alterations of non-varicose and varicose veins 437 Table 1. Mean n u m b e r of valves in the external iliae and proximal femoral and long saphenous vein up to a distance of 6 cm below the saphenofemoral junction. Age
men
women
under 40 41-60 over 60
4.3 3.6 4.4
4.3 4.3 4.0
Total
4.1
4.1
4
5-6
9 9
13 16
10 13
18
29
23
Age
n u m b e r of valves 2-3
under 60 a over
60 b
Total
a, b = no statistical difference between the n u m b e r of valves (x2-Test).
T a b l e 1 s h o w s t h a t t h e n u m b e r of v a l v e s w a s e q u a l i n b o t h s e x e s . T h e n u m b e r of valves was not r e d u c e d in the a d v a n c e d age groups. Within the i n d i v i d u a l v a r i a t i o n w i d t h , t h e a m o u n t of v a l v e s r e m a i n e d c o n s t a n t in all age groups. Light microscope examination did not reveal any fibrotic a l t e r a t i o n s of t h e v a l v e s e v e n in t h e h i g h e s t a g e g r o u p s . T h e s o - c a l l e d m a i n v a l v e of t h e l o n g s a p h e n o u s v e i n w a s p r e s e n t i n all c a s e s . I t w a s s i t u a t e d d i r e c t l y at t h e s a p h e n o - f e m o r a l j u n c t i o n i n 89%, w i t h i n 0.5 c m b e l o w t h e j u n c t i o n i n 8% a n d w i t h i n 1 c m b e l o w t h e j u n c t i o n in 3%. T h e f e m o r a l vein s e g m e n t b e l o w the s a p h e n o - f e m o r a l j u n c t i o n cont a i n e d o n e v a l v e w i t h i n 3-6 c m b e l o w t h e j u n c t i o n in 86% of t h e c a s e s .
Fig. 2. Intimal thickening in a non-varicose superficial vein. Elastin, 200•
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Basic Research in Cardiology, VoI. 74, No. 4 (1979)
T a b l e 2. I n t i m a l f i b r o s i s of t h e l o n g s a p h e n o u s v e i n of 52 s u b j e c t s of v a r i o u s age. 25 m e n / 2 7 w o m e n , m e a n a g e 56.9 years. Age
men ++
0-40 41-60 61-90
% §+ + (+) -
women ++ + (+)
-
total ++ + (+)
+ (+)
-
-
1 1 1
1 4 8
0 3 3
2 0 1
0 1 1
1 4 8
0 1 5
3 1 2
1 2 2
2 8 16
0 4 8
5 1 3
3 12
13 52
6 24
3 12
2 8
13 48
6 22
6 22
5 10
26 50
12 23
9 17
S e v e r e c o n c e n t r i c i n t i m a l fibrosis, s p l i t t i n g u p of t h e i n t e r n a l elastic lamella. M o d e r a t e e x c e n t r i c i n t i m a l fibrosis. Slight intimal cushions. No a l t e r a t i o n .
The
femoral
vein
segment above
the s a p h e n o - f e m o r a l j u n c t i o n
t o g e t h e r w i t h t h e e x t e r n a l iliac vein c o n t a i n e d a t l e a s t o n e b u t n e v e r m o r e than two valves in 81% of the cases. This valve was usually situated between 2 and 4 cm above the sapheno-femoral junction. 19% of the cases had no valves in these two segments.
G r o u p 2a: L o n g s a p h e n o u s vein Fibrotic wall changes were a common finding in subjects of all age g r o u p s w i t h o u t v e n o u s d i s o r d e r s . I n t i m a l fibrosis (table 2) w a s f o u n d i n 8 3 % o f a l l c a s e s . I t s f r e q u e n c y i n c r e a s e d f r o m 25 t o 5 0 % i n t h e a g e g r o u p s b e l o w 40 t o 1 0 0 % i n t h e a g e g r o u p s a b o v e 70. N o c o r r e l a t i o n b e t w e e n a g e and degree could be detected. A marked intimal fibrosis was occasionally f o u n d i n s u b j e c t s b e l o w 20. O n t h e o t h e r h a n d , 2 0 % o f t h e s u b j e c t s b e t w e e n 60 a n d 70 h a d n o i n t i m a l f i b r o s i s a t all. 8 8 % o f t h e m e n a n d 7 8 % o f
Fig. 3. Varicose vein with slight intimal thickening and without fibrosis of media and adventitia. Van Gieson, 80x.
Leu et al., Morphological alterations of non-varicose and varicose veins 439 Table 3. Intimal fibrosis in the various segments of the long saphenous vein. Age group
0-40 41-60 61-90
%
proximal ++ + (+)
-
middle ++ + (+)
-
distal ++ + (+)
-
2 2 4
1 8 12
0 4 9
5 1 4
1 3 4
2 7 15
0 4 8
5 1 2
1 0 6
1 8 13
2 6 5
4 1 5
8 15
21 41
13 25
10 19
8 15
24 47
12 23
8 15
7 14
22 42
13 25
10 19
t h e w o m e n w e r e a f f e c t e d b y s l i g h t t o s e v e r e d e g r e e s of i n t i m a l f i b r o s i s . F r e q u e n c y a n d d e g r e e of i n t i m a l f i b r o s i s w e r e e q u a l in all t h e s e g m e n t s of t h e l o n g s a p h e n o u s v e i n (table 3). Fibrosis of m e d i a a n d adventitia w a s l e s s f r e q u e n t (table 4). S l i g h t d e g r e e s of f i b r o s i s of t h e m e d i a w e r e f o u n d i n 33% a n d of t h e a d v e n t i t i a in 12% of t h e c a s e s . S e v e r e d e g r e e s w e r e n o t o b s e r v e d . C a s e s w i t h f i b r o s i s of m e d i a and a d v e n t i t i a usually also had i n t i m a l fibrosis.
G r o u p 2b: L o w e r l e g branches of the l o n g s a p h e n o u s vein O f 49 s u b j e c t s , 35 h a d f i b r o t i c a l t e r a t i o n s of t h e w a l l l a y e r s a n d 14 h a d n o r m a l v e i n s . I n t i m a l f i b r o s i s a l o n e w a s p r e s e n t i n 55%, a n d f i b r o s i s of m e d i a a n d a d v e n t i t i a w a s f o u n d in 16% of t h e cases.
G r o u p 2c: E x t e r n a l iliac a n d f e m o r a l vein Of 30 s u b j e c t s (age r a n g e 65-90, a v e r a g e 76.6), 12 w e r e m a l e s a n d 18 w e r e f e m a l e s . A s l i g h t i n t i m a l t h i c k e n i n g w a s f o u n d in 29 of t h e 30 f e m o r a l v e i n s a n d in 23 of t h e 30 e x t e r n a l i l i a c v e i n s . F i b r o s i s of m e d i a a n d a d v e n t i t i a o r s e v e r e d e g r e e s of i n t i m a l f i b r o s i s w e r e n o t o b s e r v e d .
G r o u p 2d: D e e p l o w e r leg veins in a m p u t a t e d l i m b s Of 47 s u b j e c t s ( a g e r a n g e 61-84, a v e r a g e 65.4), 33 w e r e m a l e s a n d 14 were females.
Fig. 4. Varicose vein with m a r k e d fibrosis of media. Van Gieson, 80•
440
Basic Research in Cardiology, Vol. 74, No. 4 (1979) Table 4. Fibrosis of media and adventitia 0.
Age group
men
women
q-
0-40 41-60 61-90 %
_
q-
2 2 8
(0) (1) (0)
2 6 5
(4) (7) (13)
12a 48
(1) (4)
13 52
(24) (96)
0 3 2
total --
(1) (0) (4)
q-
--
4 4 14
(3) (7) (12)
2 5 10
(1) (1) (4)
6 10 19
(7) (14) (25)
55 (5) 22 19 (19) 81
(22) (81)
17 33
(6) (12)
35 67
(46) (88)
+ moderate, - none a, b = this difference is statistically significant (p < 0.025). A l l t h e 47 l i m b s h a d b e e n a m p u t a t e d b e c a u s e of a r t e r i o s c l e r o t i c g a n g r e n e . 18 c a s e s (38%) h a d n o i n t i m a l f i b r o s i s , 21 (45%) h a d s l i g h t a n d 8 (17%) h a d m a r k e d i n t i m a l f i b r o s i s . C a s e s w i t h f i b r o s i s of m e d i a a n d adventitia were not observed.
G r o u p 3: V a r i c o s e v e i n s 70 v a r i c o s e v e i n s (28 m e n a n d 43 w o m e n , a g e r a n g e 17-73, a v e r a g e 48.5) w e r e e x a m i n e d at t h e s i t e of m a c r o s c o p i c v a r i c o s e a l t e r a t i o n s . 38 w e r e v a r i c o s e l o n g s a p h e n o u s v e i n s a n d 32 w e r e p e r f o r a t o r s w i t h p r i m a r y ( v a r i c o s e ) i n s u f f i c i e n c y . T h e s e p e r f o r a t o r s b e l o n g e d t o t h e g r o u p of soc a l l e d C o c k e t t - v e i n s a t t h e d i s t a l m e d i a l r e g i o n of t h e l o w e r leg. T a b l e 5 s h o w s f r e q u e n c y a n d d e g r e e of f i b r o s i s of i n t i m a , m e d i a a n d a d v e n t i t i a . The statistical evaluation gives evidence that intimal fibrosis was more f r e q u e n t in n o n - v a r i c o s e t h a n i n v a r i c o s e v e i n s (p < 0.025)1). C o m p a r i s o n of n o n - v a r i c o s e a n d v a r i c o s e s a p h e n o u s v e i n s s h o w s a n e v e n g r e a t e r
Fig. 5. Varicose perforating vein with slight fibrosis of media. Venous valves without fibrotic alterations. Van Gieson, 80x. 1) For his help with the statistical evaluations we are indebted to Dr. Helfenstein of the Biostatistical Center of the Medical Faculty, University of Zfirich (Dir. Prof. Marthaler).
Leu et al., Morphological alterations of non-varicose and varicose veins 441 Table 5.70 cases of varicose veins. 28 men/42 women, 15-73 year mean age 48.5 years. Type
-
(+)
+
++
Intima] fibrosis Media fibrosis Adventitia fibrosis Atrophy of elastic fibers Dilatation/atrophy/ h y p ert ro p h y of muscles
22 24 61 32 0
22 21 3 9 18
23 21 6 28 48
3 4 0 1 4
70 70 70 70 70
3 17 28 17 0
12 6 2 4 13
15 9 2 11 19
2 0 0 0 0
32 32 32 32 32
19 7 33 15 0
10 15 1 5 5
8 12 4 17 29
1 4 0 1 4
38 38 38 38 38
32 insufficient perforators Intimal fibrosis Media fibrosis Adventitia fibrosis Atrophy of elastic fibers Dilatation/atrophy/ hypertrophy of muscles 38 varicose long saphenous veins Intima] fibrosis Media fibrosis Adventitia fibrosis Atrophy of elastic fibers Dilatation/atrophy/ h y p ert ro p h y of muscles -
(+) + ++
normal slight moderate severe
d i f f e r e n c e (p < 0.001). E v e n m e d i a a n d a d v e n t i t i a of n o n - v a r i c o s e v e i n s w e r e n o t l e s s f r e q u e n t l y a f f e c t e d b y f i b r o s i s t h a n t h o s e of v a r i c e s (differe n c e n o t s t a t i s t i c a l l y s i g n i f i c a n t ) . 50% of t h e v a r i c o s e l o n g s a p h e n o u s v e i n s a n d 20% of t h e i n s u f f i c i e n t p e r f o r a t o r s w e r e n o t a l t e r e d b y f i b r o s i s i n spite of m a r k e d dilatation and irregular a t r o p h y of t h e s m o o t h m u s c l e s . N o d e g e n e r a t i v e a l t e r a t i o n s of t h e v e n o u s v a l v e s , s u c h as t h e y a r e c o m m o n l y f o u n d i n c a s e s w i t h p o s t t h r o m b o t i c l e s i o n s , w e r e f o u n d in t h i s s e r i e s of p r i m a r y p e r f o r a t o r i n s u f f i c i e n c y . E v e n v e i n s w i t h m a r k e d d i l a t a t i o n c o n t a i n e d v a l v e s of n o r m a l c o n f i g u r a t i o n . N e i t h e r d i d t h e v a l v e s of the varicose long saphenous veins show fibrotic lesions.
D i s c u s s i o n
P a t h o g e n e s i s os v a r i c o s e v e i n s Role of venous valves A s it is s h o w n i n t a b l e l, v e n o u s v a l v e s d o n o t d e c r e a s e in n u m b e r w i t h a d v a n c i n g age. T h i s is a s t r o n g a r g u m e n t a g a i n s t t h e o p i n i o n (4, 10, 13) t h a t t h e v a l v e s s h a n k a n d v a n i s h d u r i n g life t i m e a n d t h a t t h i s v a l v u l a r
442
Basic Research in Cardiology, VoI. 74, No. 4 (1979)
insufficiency initiates t h e d e v e l o p m e n t of varicose veins. A p a r t f r o m t h e fact that there is n o statistically significant difference b e t w e e n the n u m b e r of valves in y o u n g e r a n d older age groups, h i s t o l o g y did n o t reveal a n y i m p o r t a n t d e g e n e r a t i v e alterations of the v e n o u s valves at old age. This is a f u r t h e r i n d i c a t i o n that the valves do not play a n i m p o r t a n t role in p a t h o g e n e s i s of p r i m a r y varicose veins. E x c e p t i o n s are cases of s e c o n d a r y varicose veins d u e to c o n g e n i t a l a b s e n c e of d e e p v e n o u s valves (8, 9) or p o s t t h r o m b o t i c fibrous s h r i n k i n g of the valves. T h e fact t h a t 19% of t h e subjects h a d no valves in the e x t e r n a l iliac vein a n d the p r o x i m a l s e g m e n t of the f e m o r a l vein w i t h o u t a n y clinical s y m p t o m s of v e n o u s stasis suggests that the valves in t h e s e s e g m e n t s are of m i n o r i m p o r t a n c e for the v e n o u s reflux. T h e so-called m a i n valve of the long s a p h e n o u s vein s e e m s to have a n i m p o r t a n t function. It was f o u n d in all cases. I n the m a j o r i t y of the cases it was situated directly at the s a p h e n o - f e m o r a l junction, in t h e o t h e r cases it lay w i t h i n 1 c m b e l o w t h e junction. Role of intimal fibrosis
I n t i m a l fibrosis of the superficial leg veins is a c o m m o n finding in all age groups. It is n o t restricted to varicose veins. It was e v e n m o r e f r e q u e n t in n o n - v a r i c o s e t h a n in varicose veins. I n n o n - v a r i c o s e veins it was sometimes f o u n d already in subjects b e l o w 30 a n d it was p r e s e n t in at least a slight d e g r e e in all subjects over 70. A correlation b e t w e e n age a n d degree, h o w e v e r , did not exist. T h e s e findings s u g g e s t that intimal fibrosis is no p a t h o g e n e t i c factor for the d e v e l o p m e n t of varicose veins. Role of fibrosis of media and adventitia
I n n o n - v a r i c o s e veins, fibrosis of m e d i a a n d adventitia is less f r e q u e n t t h a n intimal fibrosis a n d does n o t r e a c h severe degrees. I n our material it was m o r e f r e q u e n t in m e n t h a n in w o m e n (this difference is statistically significant (p < 0.025). We have no e x p l a n a t i o n for this difference. I n varicose veins with large dilatations a n d m a r k e d a t r o p h y of the s m o o t h muscles, fibrosis of m e d i a a n d adventitia is a c o m m o n finding. It is r e m a r k a b l e , h o w e v e r , that 50% of the varicose l o n g s a p h e n o u s veins a n d 20% of the insufficient p e r f o r a t o r s h a d n o fibrosis of m e d i a a n d adventitia even in s e g m e n t s w i t h dilatation a n d s m o o t h m u s c l e atrophy. T h e r e was no statistically significant difference b e t w e e n the a m o u n t of fibrosis in m e d i a a n d adventitia of n o n - v a r i c o s e a n d of varicose veins. This indicates t h a t fibrosis of m e d i a a n d adventitia is no p r e r e q u i s i t e for the d e v e l o p m e n t of varicose veins. S u c h lesions o c c u r only at a later stage w h e n t h e a t r o p h i c m u s c u l a t u r e is i n c r e a s i n g l y r e p l a c e d b y collagen fibers. All these findings are in a c c o r d a n c e to t h e o p i n i o n (12, 14) that a p r i m a r y d e f i c i e n c y of the v e n o u s wall c o m p o n e n t s causes a loss of t o n e of the s m o o t h m u s c l e s followed b y dilatation of the vein. T h e loss of t o n e is at first p a r t l y c o m p e n s a t e d b y h y p e r t r o p h y of the m u s c u l a r wall layers, b u t finally results in a t r o p h y a n d fibrous d e g e n e r a t i o n of t h e wall. T h e valvular insufficiency is f u n c t i o n a l a n d s e c o n d a r y . It is d u e to the dilatation of
Leu et al., Morphological alterations of non-varicose and varicose veins 443 t h e lumen. E v e n t h e v e n o u s valves r e m a i n s m o o t h a n d s l e n d e r a n d do n o t u n d e r g o serious d e g e n e r a t i v e changes. This is in a c c o r d a n c e to the opinion of F e g a n (2) t h a t v e n o u s valves r e s u m e a perfectly n o r m a l f u n c t i o n if the caliber of t h e vein is n o r m a l i z e d (varicose veins in p r e g n a n c y ) . I n f l u e n c e o f arteriosclerosis on a d j a c e n t veins It was a r g u e d (ll) that arteriosclerosis has an influence on the a d j a c e n t deep veins a n d i n d u c e s fibrous t h i c k e n i n g of the vein wall followed b y severe v e n o u s insufficiency. I n o u r series the d e e p leg veins w e r e not seriously altered at old age. S o m e slight degree of intimal fibrosis could be f o u n d in s o m e of t h e cases. E v e n in l i m b s w h i c h h a d b e e n a m p u t a t e d d u e to arteriosclerotic gangrene, t h e m a j o r i t y of the d e e p veins was n o r m a l or s h o w e d only slight intimal proliferation. This indicates that t h e d e e p leg veins are n o t seriously i n f l u e n c e d b y sclerosis of the arteries w i t h i n the c o m m o n v a s c u l a r s h e a t h a n d that v e n o u s i n s u f f i c i e n c y is h a r d l y ever d u e to sclerotic lesions of the a d j a c e n t arteries.
R o l e o f intirnaI fibrosis in a u t o g e n o u s vein grafts The long s a p h e n o u s vein is the favourite a u t o g e n o u s graft vein u s e d for r e c o n s t r u c t i v e s u r g e r y of p e r i p h e r a l a n d c o r o n a r y arteries. As w e h a v e f o u n d , all s e g m e n t s of t h e l o n g s a p h e n o u s vein are f r e q u e n t l y affected b y intimal fibrosis e v e n in y o u n g subjects. It does n o t follow t h a t graft veins w i t h intimal proliferations are necessarily insufficient material. As w e h a v e p o i n t e d o u t earlier (1, 6), a b u n d a n t intimal proliferation in a u t o g e n ous graft veins is one of the c o m p l i c a t i o n s w h i c h m a y lead to n a r r o w i n g a n d s u b s e q u e n t t h r o m b o s i s . O v e r s h o o t i n g intimal proliferation is n o t d e p e n d e n t of the age of the p a t i e n t or the age of the graft. W h e t h e r p r e e x i s t i n g intimal fibrosis in a u t o g e n o u s graft veins m a y be o n e of several factors w h i c h i n d u c e a b u n d a n t intimal proliferation is n o t clear.
Zusammenfassung Die Venenklappen spielen keine Rolle in der Pathogenese der prirn~ren Varizen. Ihre Anzahl bleibt w~ihrend des Lcbens konstant. In varik6sen V e n e n werden sie erst sekund~ir insuffizient. Die Intimafibrose ist keine Vorbedingung f~r die Entwicklung von Varizen. Sie ist ein h~ufiger Befund in nichtvarik6sen V e n e n jeden Lebensalters. Die Fibrose der Media u n d Adventitia ist keine morphologische Fr~hver'~nde-
rung in Varizen. Der fibr6se Ersatz der glatten Muskulatur tritt erst in sp~iteren Stadien der Varikosis in Erscheinung. Degenerative Ver~inderungen an den tiefen Beinvenen sind selbst im hohen Lebensalter selten. Die tiefen Beinvenen werden durch Sklerose der benachbarten Arterien nicht beeinflu6t. Vorbestehende Intimafibrose in Venen, die als autologe Transplantate verwendet werden, kann einer yon vielen Faktoren sein, die eine fiberschiel3ende Intimaproliferation einleiten. Degenerative Wandver'&nderungen (Fibrose der Wandschichten, Insuffizienz der Venenklappen) sind sekund~ire Ph~inomene in der Pathogenese der Varizen. Sie treten erst im Gefolge einer funktionellen Insuffizienz der glatten Muskulatur in Erscheinung.
444
Basic Research in Cardiology, Vol. 74, No. 4 (1979) References
i. Brunner, U., H. J. Leu: Postrekonstruktive ,,Service-Operationen" mit autologem Material. Vorirag an der 1. Gemeinschaftstagung der Angiologisehen Gesellschaft der B R D , Schweiz und 0sterreich. Wien 20.-23.9. 1977 (EongreBband). 2. Fegan, G.: Varicose veins: compression selerotherapy (London 1967). 3. Johnson, If. D., J. Pflug: The swollen leg (London 1975). 4. K1~ken, N., in: F61di, IVZ, IV. Kldken, IVZ Collard: Praxis der LymphgefiiS- und Venenerkrankungen (Stuttgart 1974). 5. Leu, H. J., U. Brunner, E. Wyss: So-called "service-operations" in reconstructive vascular surgery (in print). 6. Leu, S. J., U. Brunner: Zur Pathogenese der degenerativen Ver~nderungen an autologen Venentransplantaten. Dtsch. ivied. Wsehr. 51, 2433 (1973). 7. Leu, S. J.: I-~stopathologie der peripheren Venenerkrankungen (Bern, Stuttgart, Wien 1971). 8. Lodin, A.: Congenital absence of valves in the deep veins of the leg, Part I, Acta Dermato-Venerologica, Vol. 41, Suppl. 45 (Stockholm 1961). 9. Llndva11, N., A. Lodln: Congenital absence of valves in the deep veins of the leg, Part II, Acta Dermato-Venerologica Vol. 41, Suppl. 45 (Stockholm 1961). 1O. Myers, T. T., in: Allen, E. V., N. W. Barker, E. A. Hines: Peripheral vascular diseases, 3rd ed. (Philadelphia and L o n d o n 1962). 11. Schoblnger, R. A.: Arteriosklerotische Venopathie. Zbl. Phlebol. 4, 102 (1965). 12. Staubesand, J.: Matrixvesikel und Mediadysplasie: ein neues Konzept zur formalen P a t h o g e n e s e der Varikose. Phlebol. u n d Proktol. 7, 109 (1978). 13. Thurner, J., R. May: P r o b l e m e der Phlobopathologie mit besonderer Berficksichtigung der Phleboslderose. Zbl. Phlebol. 6, 404 (1967). 14. Thulesius, (9.: Pathogenesis of varicose veins, Vortrag am: European-American s y m p o s i u m on v e n o u s diseases, Zi~rich, 4.-8. Sept. 1978, Abstract Nr. 68. 15. Widmer, L. K. et al: Peripheral venous disorders (Bern, Stuttgart, Wien 1978). Authors' address: Prof. Dr. reed. H. J. Leu, Institut fiir Pathologie, Universit~it Ziirich, Sehmelzbergs t r a f e 12, CH-8091 Zfirich
Insitut f~r Pathologie, Universit~t Z~rich (Direktoren: Prof. Chr. Hedinger/Prof. J. R. RiJttner)
M o r p h o l o g i c a l a l t e r a t i o n s of n o n - v a r i c o s e a n d varicose veins (A m o r p h o l o g i c a l c o n t r i b u t i o n to the d i s c u s s i o n on p a t h o g e n e s i s of v a r i c o s e veins)
M o r p h o l o g i s c h e Ver~inderungen in n i c h t v a r i k 6 s e n u n d in v a r i k 6 s e n V e n e n (Ein morphologischer Beitrag zur Diskussion Pathogenese der Varikosis)
H. J. Leu,
M. Vogt,
fiber die
and H. Pfrunder
With 5 figures and 5 tables (Received December 20, 1978)
Summary Venous valves do not play a role in pathogenesis of primary varicose veins. Their n u m b e r remains constant during life time. I n varicose veins their insufficiency is secondary. Intimal fibrosis is no prerequisite for the development of varicose veins. It is a frequent finding in non-varicose veins of all age groups. Fibrosis of media and adventitia is no early morphological alteration in varicose veins. Fibrotic replacement of smooth muscles represents a late stage of varicosis. Degenerative lesions of deep leg veins are rare even at old age. The deep veins are not influenced by sclerotic lesions of the adjacent arteries. Preexisting intimal fibrosis in autogenous graft veins may be one of several factors which induce an overshooting intimal proliferation. Degenerative alterations (fibrotic lesions of the wall layers, insufficiency of the valves) are secondary p h e n o m e n a in pathogenesis of varicose veins which follow a functional deficiency of the smooth musculature.
E t i o l o g y a n d p a t h o g e n e s i s of v a r i c o s i s a r e still o p e n to d i s c u s s i o n . I n t h e l a s t d e c a d e , e p i d e m i o l o g i c a l i n v e s t i g a t i o n s h a v e s h o w n t h a t a g i n g is t h e m a i n e t i o l o g i c a l f a c t o r w h e r e a s t h e i n f l u e n c e of sex, p r e g n a n c y , o b e s i t y a n d o c c u p a t i o n h a s b e e n o v e r r a t e d (15). A s far as p a t h o g e n e s i s is c o n c e r n e d , s o m e a u t h o r s (4, 10, 13) b e l i e v e t h a t a d e c r e a s e i n n u m b e r of v e n o u s v a l v e s is r e s p o n s i b l e for t h e d e v e l o p m e n t of v a r i c o s e v e i n s . O t h e r s c o n s i d e r d e g e n e r a t i v e w a l l l e s i o n s as t h e p r i m a r y f a c t o r (3, 7, 12, 14). As a m o r p h o l o g i c a l c o n t r i b u t i o n to this d i s c u s s i o n we h a v e investig a t e d s u p e r f i c i a l a n d d e e p v e i n s of t h e l o w e r e x t r e m i t i e s of a t o t a l of 178 s u b j e c t s w i t h o u t v e n o u s d i s o r d e r s a n d of 70 s u b j e c t s w i t h p r i m a r y varicose veins.
436
Basic Research in Cardiology, Vol. 74, No. 4 (1979)
Material and m e t h o d Our investigation included: 1. n u m b e r , l o c a l i z a t i o n a n d h i s t o l o g y of v e n o u s v a l v e s in t h e e x t e r n a l iliac a n d t h e p r o x i m a l s e g m e n t s of t h e f e m o r a l a n d l o n g s a p h e n o u s v e i n i n 70 s u b j e c t s of various age without venous disorders; 2. n u m b e r , l o c a l i z a t i o n a n d d e g r e e of d e g e n e r a t i v e wall l e s i o n s a) in t h e p r o x i m a l , m i d d l e a n d d i s t a l s e g m e n t s of t h e l o n g s a p h e n o u s v e i n of 52 s u b j e c t s of v a r i o u s a g e w i t h o u t v e n o u s d i s o r d e r s , b) in t h e s u p e r f i c i a l s a p h e n o u s b r a n c h e s of t h e l o w e r leg of 49 s u b j e c t s a b o v e t h e a g e of 40, c) i n t h e iliac a n d f e m o r a l v e i n of 30 s u b j e c t s , d) i n t h e d e e p l o w e r leg v e i n s of 47 l i m b s w h i c h h a d b e e n a m p u t a t e d d u e to arteriosclerotic gangrene; 3. t h e d e g r e e of d e g e n e r a t i v e wall l e s i o n s i n 70 v a r i c o s e veins. T h e m a t e r i a l of g r o u p 1 a n d 2a, b, c w a s o b t a i n e d a t a u t o p s y . C a s e s w i t h a n a m n e s t i c d a t a or m a c r o s c o p i c s i g n s of old or f r e s h v e n o u s d i s o r d e r s w e r e excluded. The veins were carefully removed and dissected. Number and distribut i o n of t h e v a l v e s w e r e n o t e d . H i s t o l o g y c o n s i s t e d of l i g h t m i c r o s c o p e e x a m i n a t i o n at v a r i o u s sites (stains: h e m a l a u n - e o s i n , v a n G i e s o n , e l a s t i n , o r c e i n a n d a l c i a n b l u e PAS). T h e m a t e r i a l of g r o u p 2 d w a s o b t a i n e d f r o m a m p u t a t e d l i m b s w i t h a r t e r i o sclerotic gangrene. The deep veins together with the deep lymph collectors were r e m o v e d a n d e x a m i n e d a t v a r i o u s sites. T h e m a t e r i a l of g r o u p 3 c o n s i s t e d of s u r g i c a l l y r e m o v e d v a r i c o s e v e i n s . 38 v e i n s w e r e v a r i c o s e l o n g s a p h e n o u s v e i n s a n d 32 w e r e p r i m a r y i n s u f f i c i e n t p e r f o r a t o r s s i t u a t e d at t h e m e d i a l d i s t a l r e g i o n of t h e l o w e r leg ( C o c k e t t p e r f o r a t o r s ) . (For s u p p l y of t h i s m a t e r i a l w e a r e i n d e p t e d to Prof. U. B r u n n e r , U n i v e r s i t y H o s p i t a l Zilrich, Dr. R. Fischer, R e g i o n a l H o s p i t a l W a t t w i l a n d Dr. W. MiHler, R e g i o n a l H o s p i t a l Brugg).
Results G r o u p 1: V e n o u s v a l v e s O f t h e 70 s u b j e c t s , 32 w e r e m e n a n d 38 w e r e w o m e n . 9 w e r e b e l o w t h e a g e o f 40, 23 w e r e b e t w e e n 40 a n d 60, a n d 38 w e r e b e t w e e n 61 a n d 90 y e a r s of age.
Fig. 1. N o n - v a r i c o s e s u p e r f i c i a l v e i n w i t h p r o m i n e n t i n t i m a l f i b r o s i s a n d s l i g h t f i b r o s i s of m e d i a a n d a d v e n t i t i a . V a n G i e s o n , 30•
L e u et al., Morphological alterations of non-varicose and varicose veins 437 Table 1. Mean n u m b e r of valves in the external iliae and proximal femoral and long saphenous vein up to a distance of 6 cm below the saphenofemoral junction. Age
men
women
under 40 41-60 over 60
4.3 3.6 4.4
4.3 4.3 4.0
Total
4.1
4.1
4
5-6
9 9
13 16
10 13
18
29
23
Age
n u m b e r of valves 2-3
under 60 a over
60 b
Total
a, b = no statistical difference between the n u m b e r of valves (x2-Test).
T a b l e 1 s h o w s t h a t t h e n u m b e r of v a l v e s w a s e q u a l i n b o t h s e x e s . T h e n u m b e r of valves was not r e d u c e d in the a d v a n c e d age groups. Within the i n d i v i d u a l v a r i a t i o n w i d t h , t h e a m o u n t of v a l v e s r e m a i n e d c o n s t a n t in all age groups. Light microscope examination did not reveal any fibrotic a l t e r a t i o n s of t h e v a l v e s e v e n in t h e h i g h e s t a g e g r o u p s . T h e s o - c a l l e d m a i n v a l v e of t h e l o n g s a p h e n o u s v e i n w a s p r e s e n t i n all c a s e s . I t w a s s i t u a t e d d i r e c t l y at t h e s a p h e n o - f e m o r a l j u n c t i o n i n 89%, w i t h i n 0.5 c m b e l o w t h e j u n c t i o n i n 8% a n d w i t h i n 1 c m b e l o w t h e j u n c t i o n in 3%. T h e f e m o r a l vein s e g m e n t b e l o w the s a p h e n o - f e m o r a l j u n c t i o n cont a i n e d o n e v a l v e w i t h i n 3-6 c m b e l o w t h e j u n c t i o n in 86% of t h e c a s e s .
Fig. 2. Intimal thickening in a non-varicose superficial vein. Elastin, 200•
438
Basic Research in Cardiology, VoI. 74, No. 4 (1979)
T a b l e 2. I n t i m a l f i b r o s i s of t h e l o n g s a p h e n o u s v e i n of 52 s u b j e c t s of v a r i o u s age. 25 m e n / 2 7 w o m e n , m e a n a g e 56.9 years. Age
men ++
0-40 41-60 61-90
% §+ + (+) -
women ++ + (+)
-
total ++ + (+)
+ (+)
-
-
1 1 1
1 4 8
0 3 3
2 0 1
0 1 1
1 4 8
0 1 5
3 1 2
1 2 2
2 8 16
0 4 8
5 1 3
3 12
13 52
6 24
3 12
2 8
13 48
6 22
6 22
5 10
26 50
12 23
9 17
S e v e r e c o n c e n t r i c i n t i m a l fibrosis, s p l i t t i n g u p of t h e i n t e r n a l elastic lamella. M o d e r a t e e x c e n t r i c i n t i m a l fibrosis. Slight intimal cushions. No a l t e r a t i o n .
The
femoral
vein
segment above
the s a p h e n o - f e m o r a l j u n c t i o n
t o g e t h e r w i t h t h e e x t e r n a l iliac vein c o n t a i n e d a t l e a s t o n e b u t n e v e r m o r e than two valves in 81% of the cases. This valve was usually situated between 2 and 4 cm above the sapheno-femoral junction. 19% of the cases had no valves in these two segments.
G r o u p 2a: L o n g s a p h e n o u s vein Fibrotic wall changes were a common finding in subjects of all age g r o u p s w i t h o u t v e n o u s d i s o r d e r s . I n t i m a l fibrosis (table 2) w a s f o u n d i n 8 3 % o f a l l c a s e s . I t s f r e q u e n c y i n c r e a s e d f r o m 25 t o 5 0 % i n t h e a g e g r o u p s b e l o w 40 t o 1 0 0 % i n t h e a g e g r o u p s a b o v e 70. N o c o r r e l a t i o n b e t w e e n a g e and degree could be detected. A marked intimal fibrosis was occasionally f o u n d i n s u b j e c t s b e l o w 20. O n t h e o t h e r h a n d , 2 0 % o f t h e s u b j e c t s b e t w e e n 60 a n d 70 h a d n o i n t i m a l f i b r o s i s a t all. 8 8 % o f t h e m e n a n d 7 8 % o f
Fig. 3. Varicose vein with slight intimal thickening and without fibrosis of media and adventitia. Van Gieson, 80x.
Leu et al., Morphological alterations of non-varicose and varicose veins 439 Table 3. Intimal fibrosis in the various segments of the long saphenous vein. Age group
0-40 41-60 61-90
%
proximal ++ + (+)
-
middle ++ + (+)
-
distal ++ + (+)
-
2 2 4
1 8 12
0 4 9
5 1 4
1 3 4
2 7 15
0 4 8
5 1 2
1 0 6
1 8 13
2 6 5
4 1 5
8 15
21 41
13 25
10 19
8 15
24 47
12 23
8 15
7 14
22 42
13 25
10 19
t h e w o m e n w e r e a f f e c t e d b y s l i g h t t o s e v e r e d e g r e e s of i n t i m a l f i b r o s i s . F r e q u e n c y a n d d e g r e e of i n t i m a l f i b r o s i s w e r e e q u a l in all t h e s e g m e n t s of t h e l o n g s a p h e n o u s v e i n (table 3). Fibrosis of m e d i a a n d adventitia w a s l e s s f r e q u e n t (table 4). S l i g h t d e g r e e s of f i b r o s i s of t h e m e d i a w e r e f o u n d i n 33% a n d of t h e a d v e n t i t i a in 12% of t h e c a s e s . S e v e r e d e g r e e s w e r e n o t o b s e r v e d . C a s e s w i t h f i b r o s i s of m e d i a and a d v e n t i t i a usually also had i n t i m a l fibrosis.
G r o u p 2b: L o w e r l e g branches of the l o n g s a p h e n o u s vein O f 49 s u b j e c t s , 35 h a d f i b r o t i c a l t e r a t i o n s of t h e w a l l l a y e r s a n d 14 h a d n o r m a l v e i n s . I n t i m a l f i b r o s i s a l o n e w a s p r e s e n t i n 55%, a n d f i b r o s i s of m e d i a a n d a d v e n t i t i a w a s f o u n d in 16% of t h e cases.
G r o u p 2c: E x t e r n a l iliac a n d f e m o r a l vein Of 30 s u b j e c t s (age r a n g e 65-90, a v e r a g e 76.6), 12 w e r e m a l e s a n d 18 w e r e f e m a l e s . A s l i g h t i n t i m a l t h i c k e n i n g w a s f o u n d in 29 of t h e 30 f e m o r a l v e i n s a n d in 23 of t h e 30 e x t e r n a l i l i a c v e i n s . F i b r o s i s of m e d i a a n d a d v e n t i t i a o r s e v e r e d e g r e e s of i n t i m a l f i b r o s i s w e r e n o t o b s e r v e d .
G r o u p 2d: D e e p l o w e r leg veins in a m p u t a t e d l i m b s Of 47 s u b j e c t s ( a g e r a n g e 61-84, a v e r a g e 65.4), 33 w e r e m a l e s a n d 14 were females.
Fig. 4. Varicose vein with m a r k e d fibrosis of media. Van Gieson, 80•
440
Basic Research in Cardiology, Vol. 74, No. 4 (1979) Table 4. Fibrosis of media and adventitia 0.
Age group
men
women
q-
0-40 41-60 61-90 %
_
q-
2 2 8
(0) (1) (0)
2 6 5
(4) (7) (13)
12a 48
(1) (4)
13 52
(24) (96)
0 3 2
total --
(1) (0) (4)
q-
--
4 4 14
(3) (7) (12)
2 5 10
(1) (1) (4)
6 10 19
(7) (14) (25)
55 (5) 22 19 (19) 81
(22) (81)
17 33
(6) (12)
35 67
(46) (88)
+ moderate, - none a, b = this difference is statistically significant (p < 0.025). A l l t h e 47 l i m b s h a d b e e n a m p u t a t e d b e c a u s e of a r t e r i o s c l e r o t i c g a n g r e n e . 18 c a s e s (38%) h a d n o i n t i m a l f i b r o s i s , 21 (45%) h a d s l i g h t a n d 8 (17%) h a d m a r k e d i n t i m a l f i b r o s i s . C a s e s w i t h f i b r o s i s of m e d i a a n d adventitia were not observed.
G r o u p 3: V a r i c o s e v e i n s 70 v a r i c o s e v e i n s (28 m e n a n d 43 w o m e n , a g e r a n g e 17-73, a v e r a g e 48.5) w e r e e x a m i n e d at t h e s i t e of m a c r o s c o p i c v a r i c o s e a l t e r a t i o n s . 38 w e r e v a r i c o s e l o n g s a p h e n o u s v e i n s a n d 32 w e r e p e r f o r a t o r s w i t h p r i m a r y ( v a r i c o s e ) i n s u f f i c i e n c y . T h e s e p e r f o r a t o r s b e l o n g e d t o t h e g r o u p of soc a l l e d C o c k e t t - v e i n s a t t h e d i s t a l m e d i a l r e g i o n of t h e l o w e r leg. T a b l e 5 s h o w s f r e q u e n c y a n d d e g r e e of f i b r o s i s of i n t i m a , m e d i a a n d a d v e n t i t i a . The statistical evaluation gives evidence that intimal fibrosis was more f r e q u e n t in n o n - v a r i c o s e t h a n i n v a r i c o s e v e i n s (p < 0.025)1). C o m p a r i s o n of n o n - v a r i c o s e a n d v a r i c o s e s a p h e n o u s v e i n s s h o w s a n e v e n g r e a t e r
Fig. 5. Varicose perforating vein with slight fibrosis of media. Venous valves without fibrotic alterations. Van Gieson, 80x. 1) For his help with the statistical evaluations we are indebted to Dr. Helfenstein of the Biostatistical Center of the Medical Faculty, University of Zfirich (Dir. Prof. Marthaler).
Leu et al., Morphological alterations of non-varicose and varicose veins 441 Table 5.70 cases of varicose veins. 28 men/42 women, 15-73 year mean age 48.5 years. Type
-
(+)
+
++
Intima] fibrosis Media fibrosis Adventitia fibrosis Atrophy of elastic fibers Dilatation/atrophy/ h y p ert ro p h y of muscles
22 24 61 32 0
22 21 3 9 18
23 21 6 28 48
3 4 0 1 4
70 70 70 70 70
3 17 28 17 0
12 6 2 4 13
15 9 2 11 19
2 0 0 0 0
32 32 32 32 32
19 7 33 15 0
10 15 1 5 5
8 12 4 17 29
1 4 0 1 4
38 38 38 38 38
32 insufficient perforators Intimal fibrosis Media fibrosis Adventitia fibrosis Atrophy of elastic fibers Dilatation/atrophy/ hypertrophy of muscles 38 varicose long saphenous veins Intima] fibrosis Media fibrosis Adventitia fibrosis Atrophy of elastic fibers Dilatation/atrophy/ h y p ert ro p h y of muscles -
(+) + ++
normal slight moderate severe
d i f f e r e n c e (p < 0.001). E v e n m e d i a a n d a d v e n t i t i a of n o n - v a r i c o s e v e i n s w e r e n o t l e s s f r e q u e n t l y a f f e c t e d b y f i b r o s i s t h a n t h o s e of v a r i c e s (differe n c e n o t s t a t i s t i c a l l y s i g n i f i c a n t ) . 50% of t h e v a r i c o s e l o n g s a p h e n o u s v e i n s a n d 20% of t h e i n s u f f i c i e n t p e r f o r a t o r s w e r e n o t a l t e r e d b y f i b r o s i s i n spite of m a r k e d dilatation and irregular a t r o p h y of t h e s m o o t h m u s c l e s . N o d e g e n e r a t i v e a l t e r a t i o n s of t h e v e n o u s v a l v e s , s u c h as t h e y a r e c o m m o n l y f o u n d i n c a s e s w i t h p o s t t h r o m b o t i c l e s i o n s , w e r e f o u n d in t h i s s e r i e s of p r i m a r y p e r f o r a t o r i n s u f f i c i e n c y . E v e n v e i n s w i t h m a r k e d d i l a t a t i o n c o n t a i n e d v a l v e s of n o r m a l c o n f i g u r a t i o n . N e i t h e r d i d t h e v a l v e s of the varicose long saphenous veins show fibrotic lesions.
D i s c u s s i o n
P a t h o g e n e s i s os v a r i c o s e v e i n s Role of venous valves A s it is s h o w n i n t a b l e l, v e n o u s v a l v e s d o n o t d e c r e a s e in n u m b e r w i t h a d v a n c i n g age. T h i s is a s t r o n g a r g u m e n t a g a i n s t t h e o p i n i o n (4, 10, 13) t h a t t h e v a l v e s s h a n k a n d v a n i s h d u r i n g life t i m e a n d t h a t t h i s v a l v u l a r
442
Basic Research in Cardiology, VoI. 74, No. 4 (1979)
insufficiency initiates t h e d e v e l o p m e n t of varicose veins. A p a r t f r o m t h e fact that there is n o statistically significant difference b e t w e e n the n u m b e r of valves in y o u n g e r a n d older age groups, h i s t o l o g y did n o t reveal a n y i m p o r t a n t d e g e n e r a t i v e alterations of the v e n o u s valves at old age. This is a f u r t h e r i n d i c a t i o n that the valves do not play a n i m p o r t a n t role in p a t h o g e n e s i s of p r i m a r y varicose veins. E x c e p t i o n s are cases of s e c o n d a r y varicose veins d u e to c o n g e n i t a l a b s e n c e of d e e p v e n o u s valves (8, 9) or p o s t t h r o m b o t i c fibrous s h r i n k i n g of the valves. T h e fact t h a t 19% of t h e subjects h a d no valves in the e x t e r n a l iliac vein a n d the p r o x i m a l s e g m e n t of the f e m o r a l vein w i t h o u t a n y clinical s y m p t o m s of v e n o u s stasis suggests that the valves in t h e s e s e g m e n t s are of m i n o r i m p o r t a n c e for the v e n o u s reflux. T h e so-called m a i n valve of the long s a p h e n o u s vein s e e m s to have a n i m p o r t a n t function. It was f o u n d in all cases. I n the m a j o r i t y of the cases it was situated directly at the s a p h e n o - f e m o r a l junction, in t h e o t h e r cases it lay w i t h i n 1 c m b e l o w t h e junction. Role of intimal fibrosis
I n t i m a l fibrosis of the superficial leg veins is a c o m m o n finding in all age groups. It is n o t restricted to varicose veins. It was e v e n m o r e f r e q u e n t in n o n - v a r i c o s e t h a n in varicose veins. I n n o n - v a r i c o s e veins it was sometimes f o u n d already in subjects b e l o w 30 a n d it was p r e s e n t in at least a slight d e g r e e in all subjects over 70. A correlation b e t w e e n age a n d degree, h o w e v e r , did not exist. T h e s e findings s u g g e s t that intimal fibrosis is no p a t h o g e n e t i c factor for the d e v e l o p m e n t of varicose veins. Role of fibrosis of media and adventitia
I n n o n - v a r i c o s e veins, fibrosis of m e d i a a n d adventitia is less f r e q u e n t t h a n intimal fibrosis a n d does n o t r e a c h severe degrees. I n our material it was m o r e f r e q u e n t in m e n t h a n in w o m e n (this difference is statistically significant (p < 0.025). We have no e x p l a n a t i o n for this difference. I n varicose veins with large dilatations a n d m a r k e d a t r o p h y of the s m o o t h muscles, fibrosis of m e d i a a n d adventitia is a c o m m o n finding. It is r e m a r k a b l e , h o w e v e r , that 50% of the varicose l o n g s a p h e n o u s veins a n d 20% of the insufficient p e r f o r a t o r s h a d n o fibrosis of m e d i a a n d adventitia even in s e g m e n t s w i t h dilatation a n d s m o o t h m u s c l e atrophy. T h e r e was no statistically significant difference b e t w e e n the a m o u n t of fibrosis in m e d i a a n d adventitia of n o n - v a r i c o s e a n d of varicose veins. This indicates t h a t fibrosis of m e d i a a n d adventitia is no p r e r e q u i s i t e for the d e v e l o p m e n t of varicose veins. S u c h lesions o c c u r only at a later stage w h e n t h e a t r o p h i c m u s c u l a t u r e is i n c r e a s i n g l y r e p l a c e d b y collagen fibers. All these findings are in a c c o r d a n c e to t h e o p i n i o n (12, 14) that a p r i m a r y d e f i c i e n c y of the v e n o u s wall c o m p o n e n t s causes a loss of t o n e of the s m o o t h m u s c l e s followed b y dilatation of the vein. T h e loss of t o n e is at first p a r t l y c o m p e n s a t e d b y h y p e r t r o p h y of the m u s c u l a r wall layers, b u t finally results in a t r o p h y a n d fibrous d e g e n e r a t i o n of t h e wall. T h e valvular insufficiency is f u n c t i o n a l a n d s e c o n d a r y . It is d u e to the dilatation of
Leu et al., Morphological alterations of non-varicose and varicose veins 443 t h e lumen. E v e n t h e v e n o u s valves r e m a i n s m o o t h a n d s l e n d e r a n d do n o t u n d e r g o serious d e g e n e r a t i v e changes. This is in a c c o r d a n c e to the opinion of F e g a n (2) t h a t v e n o u s valves r e s u m e a perfectly n o r m a l f u n c t i o n if the caliber of t h e vein is n o r m a l i z e d (varicose veins in p r e g n a n c y ) . I n f l u e n c e o f arteriosclerosis on a d j a c e n t veins It was a r g u e d (ll) that arteriosclerosis has an influence on the a d j a c e n t deep veins a n d i n d u c e s fibrous t h i c k e n i n g of the vein wall followed b y severe v e n o u s insufficiency. I n o u r series the d e e p leg veins w e r e not seriously altered at old age. S o m e slight degree of intimal fibrosis could be f o u n d in s o m e of t h e cases. E v e n in l i m b s w h i c h h a d b e e n a m p u t a t e d d u e to arteriosclerotic gangrene, t h e m a j o r i t y of the d e e p veins was n o r m a l or s h o w e d only slight intimal proliferation. This indicates that t h e d e e p leg veins are n o t seriously i n f l u e n c e d b y sclerosis of the arteries w i t h i n the c o m m o n v a s c u l a r s h e a t h a n d that v e n o u s i n s u f f i c i e n c y is h a r d l y ever d u e to sclerotic lesions of the a d j a c e n t arteries.
R o l e o f intirnaI fibrosis in a u t o g e n o u s vein grafts The long s a p h e n o u s vein is the favourite a u t o g e n o u s graft vein u s e d for r e c o n s t r u c t i v e s u r g e r y of p e r i p h e r a l a n d c o r o n a r y arteries. As w e h a v e f o u n d , all s e g m e n t s of t h e l o n g s a p h e n o u s vein are f r e q u e n t l y affected b y intimal fibrosis e v e n in y o u n g subjects. It does n o t follow t h a t graft veins w i t h intimal proliferations are necessarily insufficient material. As w e h a v e p o i n t e d o u t earlier (1, 6), a b u n d a n t intimal proliferation in a u t o g e n ous graft veins is one of the c o m p l i c a t i o n s w h i c h m a y lead to n a r r o w i n g a n d s u b s e q u e n t t h r o m b o s i s . O v e r s h o o t i n g intimal proliferation is n o t d e p e n d e n t of the age of the p a t i e n t or the age of the graft. W h e t h e r p r e e x i s t i n g intimal fibrosis in a u t o g e n o u s graft veins m a y be o n e of several factors w h i c h i n d u c e a b u n d a n t intimal proliferation is n o t clear.
Zusammenfassung Die Venenklappen spielen keine Rolle in der Pathogenese der prirn~ren Varizen. Ihre Anzahl bleibt w~ihrend des Lcbens konstant. In varik6sen V e n e n werden sie erst sekund~ir insuffizient. Die Intimafibrose ist keine Vorbedingung f~r die Entwicklung von Varizen. Sie ist ein h~ufiger Befund in nichtvarik6sen V e n e n jeden Lebensalters. Die Fibrose der Media u n d Adventitia ist keine morphologische Fr~hver'~nde-
rung in Varizen. Der fibr6se Ersatz der glatten Muskulatur tritt erst in sp~iteren Stadien der Varikosis in Erscheinung. Degenerative Ver~inderungen an den tiefen Beinvenen sind selbst im hohen Lebensalter selten. Die tiefen Beinvenen werden durch Sklerose der benachbarten Arterien nicht beeinflu6t. Vorbestehende Intimafibrose in Venen, die als autologe Transplantate verwendet werden, kann einer yon vielen Faktoren sein, die eine fiberschiel3ende Intimaproliferation einleiten. Degenerative Wandver'&nderungen (Fibrose der Wandschichten, Insuffizienz der Venenklappen) sind sekund~ire Ph~inomene in der Pathogenese der Varizen. Sie treten erst im Gefolge einer funktionellen Insuffizienz der glatten Muskulatur in Erscheinung.
444
Basic Research in Cardiology, Vol. 74, No. 4 (1979) References
i. Brunner, U., H. J. Leu: Postrekonstruktive ,,Service-Operationen" mit autologem Material. Vorirag an der 1. Gemeinschaftstagung der Angiologisehen Gesellschaft der B R D , Schweiz und 0sterreich. Wien 20.-23.9. 1977 (EongreBband). 2. Fegan, G.: Varicose veins: compression selerotherapy (London 1967). 3. Johnson, If. D., J. Pflug: The swollen leg (London 1975). 4. K1~ken, N., in: F61di, IVZ, IV. Kldken, IVZ Collard: Praxis der LymphgefiiS- und Venenerkrankungen (Stuttgart 1974). 5. Leu, H. J., U. Brunner, E. Wyss: So-called "service-operations" in reconstructive vascular surgery (in print). 6. Leu, S. J., U. Brunner: Zur Pathogenese der degenerativen Ver~nderungen an autologen Venentransplantaten. Dtsch. ivied. Wsehr. 51, 2433 (1973). 7. Leu, S. J.: I-~stopathologie der peripheren Venenerkrankungen (Bern, Stuttgart, Wien 1971). 8. Lodin, A.: Congenital absence of valves in the deep veins of the leg, Part I, Acta Dermato-Venerologica, Vol. 41, Suppl. 45 (Stockholm 1961). 9. Llndva11, N., A. Lodln: Congenital absence of valves in the deep veins of the leg, Part II, Acta Dermato-Venerologica Vol. 41, Suppl. 45 (Stockholm 1961). 1O. Myers, T. T., in: Allen, E. V., N. W. Barker, E. A. Hines: Peripheral vascular diseases, 3rd ed. (Philadelphia and L o n d o n 1962). 11. Schoblnger, R. A.: Arteriosklerotische Venopathie. Zbl. Phlebol. 4, 102 (1965). 12. Staubesand, J.: Matrixvesikel und Mediadysplasie: ein neues Konzept zur formalen P a t h o g e n e s e der Varikose. Phlebol. u n d Proktol. 7, 109 (1978). 13. Thurner, J., R. May: P r o b l e m e der Phlobopathologie mit besonderer Berficksichtigung der Phleboslderose. Zbl. Phlebol. 6, 404 (1967). 14. Thulesius, (9.: Pathogenesis of varicose veins, Vortrag am: European-American s y m p o s i u m on v e n o u s diseases, Zi~rich, 4.-8. Sept. 1978, Abstract Nr. 68. 15. Widmer, L. K. et al: Peripheral venous disorders (Bern, Stuttgart, Wien 1978). Authors' address: Prof. Dr. reed. H. J. Leu, Institut fiir Pathologie, Universit~it Ziirich, Sehmelzbergs t r a f e 12, CH-8091 Zfirich
