UMEÅ UNIVERSITY MEDICAL DISSERTATIONSN ew Series N o 133 - ISSN 0346-6612

From the Department of Surgery University o f Umeå, Umeå, Sweden

Familial Occurrence of Abdominal Aortic Aneurysms

by

ÖRJAN NORRGÄRD

J. 3 1

Umeå University 1985

Familial Occurrence of Abdominal Aortic Aneurysms

A K A D E M I S K A V H A N D L I N G

som med vederbörligt tillstånd av Rektorsämbetet vid Umeå universitet för avläggande av medicine doktorsexamen

kommer att offentligen försvaras i Kirurgiska klinikens föreläsningssal, byggnad 3 B, Regionsjukhuset, Umeå,

fredagen den 1 februari, 1985, kl 09.00

av

ÖRJAN NORRGÅRD

UMEA 1985

UMEÅ UNIVERSITY MEDICAL DISSERTATIONSNew S e r i e s No 133 - ISSN 0 3 4 6 -6 6 1 2

ABSTRACT

The occurrence o f c l i n i c a l l y diagnosed and/or ruptured abdominal a o r t i c aneurysms (AAAs) in the f a m i l i e s o f 220 p a t i e n t s with AAAs, t r e a te d a t the Surgica l C l i n i c , U n iv e r s i ty Hospita l o f Umeå in the northern part o f Sweden during the y ea rs 1965-82, was s tu d ie d . A q u e s t io n n a ir e concerning the blood r e l a t i v e s was answered by 87 /89 p a t i e n t s .16/87 p a t i e n t s (18%) had blood r e l a t i v e s with AAAs. In 14 f a m i l i e s one blood r e l a t i v e was a f f e c t e d , and in 2 f a m i l i e s two blood r e l a t i v e s were a f f e c t e d . F i r s t degree r e l a t i v e s were a f f e c t e d in 9 /87 ca s e s (10%), and second degree r e l a t i v e s in 7 /87 ca s e s (8%). 9 /468 (1.9%) o f the p a t i e n t s ' brothers and s i s t e r s but on ly f i v e o f a l l t h e i r c o u s in s had AAAs, and 7/204 (3.4%) o f the dead brothers and s i s t e r s had died o f ruptured AAAs. Concern­ing the p a t i e n t s who were not included in the l e t t e r survey at l e a s t 14/133had blood r e l a t i v e s with AAAs. However, the g rea t m ajor ity o f th e s e pa­t i e n t s were dead when the study was performed and could not be asked aboutthe occurrence o f AAAs in t h e i r f a m i l i e s .The p a t i e n t s with AAAs had s i g n i f i c a n t l y higher serum co n c e n tr a t io n s o f t r i g l y c e r i d e and (YLDL + L D L )-choles tero l and a s i g n i f i c a n t l y lower serum c o n c e n tr a t io n o f HDL-cholesterol than randomly s e l e c t e d h ea lthy c o n t r o l s o f the same sex and age as the p a t i e n t s .We a l s o compared the d i s t r i b u t i o n s o f g e n e t i c markers (HLA a n t ig e n s , the blood group systems ABO, Rh, MNSs, P, K e l l , Lewis and Duffy and the serum pro te in group systems h a p to g lo b in , t r a n s f e r r i n , g r o u p - s p e c i f i c component, complement C3, properdin f a c to r and a l p h a -1 - a n t i t r y p s in ) in p a t i e n t s with AAAs with the d i s t r i b u t i o n s in c o n t r o l s and in some ca s e s with the expected d i s t r i b u t i o n s according to the Hardy-Weinberg law. A s i g n i f i c a n t l y d e c r e a s ­ed frequency o f R h-negative in d i v id u a l s , and s i g n i f i c a n t l y in crea sed f r e ­quencies o f K e l l - p o s i t i ve in d i v id u a l s , o f MN h e tero zy g o tes and o f h e te r o ­z y g o tes concerning haptoglobin type was found.Furthermore, the aneurysm w a l l s o f p a t i e n t s with and without AAAs in the fam ily were compared concerning the morphology, but no d i f f e r e n c e s were found. We a l s o s tu d ied the occurrence o f c o l la g e n types I and III in the aneurysm w a l l s , and the occurrence o f vimentin and desmin in the smooth muscle c e l l s o f the aneurysm w a l l s , but a l l t h e se components were p resen t in the aneurysm w a l l s o f both the p a t i e n t s with and those w ithout AAAs in the fa m ily .To summarize the r e s u l t s , the re seems to be an in crea sed frequency o f AAAs, and e s p e c i a l l y o f ruptured AAAs, among the brothers and s i s t e r s o f p a t i e n t s with AAAs. Elevated serum c o n c e n tr a t io n s o f t r i g l y c e r i d e and (VLDL + LDL)- c h o le s t e r o l and a lowered serum c o n cen tra t io n o f HDL-cholesterol seems to be common in p a t i e n t s with AAAs. There seems to be a h ered i ta ry p r e d i s p o s i ­t i o n to the development o f AAAs, because we found a s s o c i a t i o n s with four d i f f e r e n t g e n e t ic markers (Rh, MN, K e l l , haptoglobin group). However, there i s probably no s p e c i f i c " fa m il ia l" type o f AAAs, because we found no d i f ­fe r e n c e s between the p a t i e n t s with and those w ithout AAAs in the fa m ily .

Key words: Abdominal a o r t i c aneurysms, f a m i l ia l occu rre nc e , serum l i p i d s and l i p o p r o t e i n s , g e n e t i c markers, morphology, c o l la g e n ty p e s , v im en tin , desmin.

UMEÅ UNIVERSITY MEDICAL DISSERTATIONSNew Series No 133 - ISSN 0346-6612

From the Department of Surgery University of Umeå, Umeå, Sweden

Familial Occurrence of Abdominal Aortic Aneurysms

by

ÖRJAN NORRGÅRD

Um eå U nivers i ty 1985

2

ABSTRACT

The occurrence o f c l i n i c a l l y d iagnosed and/or ruptured abdominal a o r t i c aneurysms (AAAs) in the f a m i l i e s o f 220 p a t i e n t s with AAAs, t r e a t e d a t th e S u rg ica l C l i n i c , U n iv e r s i ty H osp ita l o f Umeå in the northern part o f Sweden during the y e a r s 19 6 5 -8 2 , was s t u d ie d . A q u e s t io n n a ir e con­c e r n in g the blood r e l a t i v e s was answered by 87 /89 p a t i e n t s .16 /87 p a t i e n t s (18%) had blood r e l a t i v e s w ith AAAs. In 14 f a m i l i e s one blood r e l a t i v e was a f f e c t e d , and in 2 f a m i l i e s two blood r e l a t i v e s were a f f e c t e d . F i r s t degree r e l a t i v e s were a f f e c t e d in 9 /87 c a s e s (10%), and second degree r e l a t i v e s in 7 /87 c a s e s (8%). 9 /468 (1.9%) o f the pa­t i e n t s ' b ro th e rs and s i s t e r s but o n ly f i v e o f a l l t h e i r c o u s in s had AAAs, and 7 /204 (3.4%) o f the dead b r o th e r s and s i s t e r s had d ied o f ruptured AAAs. Concerning the p a t i e n t s who were not in c lu d ed in the l e t t e r survey a t l e a s t 1 4 / 133 had blood r e l a t i v e s with AAAs. However, the g r e a t m a jo r i ty o f t h e s e p a t i e n t s were dead when the study was per­formed and could not be asked about the o ccu rrence o f AAAs in t h e i r f a m i l i e s .The p a t i e n t s with AAAs had s i g n i f i c a n t l y h igher serum c o n c e n t r a t io n s o f t r i g l y c e r i d e and (VLDL + L D L )-ch o les ter o l and a s i g n i f i c a n t l y lower serum c o n c e n tr a t io n o f H DL-cholesterol than randomly s e l e c t e d h e a l th y c o n t r o l s o f the same se x and age as the p a t i e n t s .We a l s o compared the d i s t r i b u t i o n s o f g e n e t i c markers (HLA a n t i g e n s , the blood group system s ABO, Rh, MNSs, P, K e l l , Lewis and Duffy and the serum p r o te in group system s h a p to g lo b in , t r a n s f e r r i n , g r o u p - s p e c i f i c component, complement C3, properdin f a c t o r and a l p h a - l - a n t i t r y p s i n ) in p a t i e n t s with AAAs with th e d i s t r i b u t i o n s in c o n t r o l s and in some c a s e s with the ex p ec ted d i s t r i b u t i o n s a cco rd in g to the Hardy-Weinberg law. A s i g n i f i c a n t l y d ecreased frequency o f R h -ne gative i n d i v i d u a l s , and s i g ­n i f i c a n t l y in c r e a s e d f r e q u e n c ie s o f K e l l - p o s i t i ve i n d i v i d u a l s , o f MN h e te r o z y g o t e s and o f h e t e r o z y g o t e s con cern in g h aptog lob in type was found.Furthermore, the aneurysm w a l l s o f p a t i e n t s with and w ithou t AAAs in the fa m ily were compared con cern in g the morphology, but no d i f f e r e n c e s were found. We a l s o s t u d ie d the occurrence o f c o l la g e n types I and III in the aneurysm w a l l s , and the occurrence o f v imentin and desmin in the smooth muscle c e l l s o f the aneurysm w a l l s , but a l l t h e s e componentswere p r e s e n t in the aneurysm w a l l s o f both the p a t i e n t s with and tho sew ith o u t AAAs in the fa m i ly .To summarize the r e s u l t s , th e r e seems to be an in c r e a s e d frequency o f AAAs, and e s p e c i a l l y o f ruptured AAAs, among the b ro th e rs and s i s t e r s o f p a t i e n t s with AAAs. E lev a ted serum c o n c e n t r a t io n s o f t r i g l y c e r i d e and (VLDL + L D L )-ch o les ter o l and a lowered serum c o n c e n tr a t io n o f HDL- c h o l e s t e r o l seems to be common in p a t i e n t s with AAAs. There seems to be a h e r e d i t a r y p r e d i s p o s i t i o n to the development o f AAAs, because we found a s s o c i a t i o n s with four d i f f e r e n t g e n e t i c markers (Rh, MN, K e l l ,h a p to g lo b in group) . However, th e r e i s probably no s p e c i f i c " fa m i l ia l"type o f AAAs, because we found no d i f f e r e n c e s between the p a t i e n t s with and th o s e w ithou t AAAs in the fa m i ly .

Key words: Abdominal a o r t i c aneurysms, f a m i l i a l o c c u r r e n c e , serum l i p i d s and l i p o p r o t e i n s , g e n e t i c markers, morphology, c o l la g e n t y p e s , v im e n t in , desmin.

To Eivor and Erik

4

ABBREVIATIONS

AAA = abdominal a o r t i c aneurysm

FAAA = f a m i l i a l abdominal a o r t i c aneurysm

ICA = in tr a c r a n ia l aneurysm

VLDL = very low d e n s i t y l i p o p r o t e i n s

LDL = low d e n s i t y l i p o p r o t e i n s

HDL = high d e n s i t y l i p o p r o t e i n s

P ed igr ee = fa m ily t r e e

Proband = the in d iv id u a l from which the study o f a s p e c i f i c f a m ily

or i g in a te s

5

ORIGINAL PAPERS

This t h e s i s i s based on the f o l l o w in g p a p e r s , which are r e f e r r e d t o in

the t e x t by t h e i r Roman numerals:

I Norrgård Ö, Rais 0 , Ängquist KA.

F a m il ia l occurrence o f abdominal a o r t i c aneurysms.

Surgery 95: 6 5 0 -6 , 1984.

II Norrgård Ö, Ängquist KA, Johnson 0 .

F a m il ia l a o r t i c aneurysms-serum c o n c e n t r a t io n s o f t r i g l y c e r i d e ,

c h o l e s t e r o l , HDL-cholesterol and (VLDL + L D L ) - c h o le s t e r o l .

B r i t J Surg, Accepted fo r p u b l i c a t i o n , August 1984.

III Norrgård Ö, Cedergren B, Ä ngquist KA, Beckman L.

Blood groups and HLA a n t ig e n s in p a t i e n t s with abdominal a o r t i c

aneurysms.

Human H ered ity 34: 9 - 1 3 , 1984.

IV Norrgård Ö, Fröhlander N, Beckman G, Ä ngquist KA.

A s s o c ia t io n between h a p to g lo b in groups and a o r t i c abdominal aneu­

rysms .

Human H ered ity 34: 1 6 6 -9 , 1984.

V Thornell L-E, Norrgård Ö, Eriksson A, Vanderwee M, Ängquist KA.

F am il ia l abdominal a o r t i c aneurysms. On the d i s t r i b u t i o n o f e l a s ­

t i n , c o l l a g e n I and I I I , and the in te r m e d ia te f i la m e n t p r o t e in s

desmin and v im en tin .

Submitted fo r p u b l i c a t io n

6

CONTENTS

INTRODUCTION ............................................................................................................................. 7

AIMS OF THE INVESTIGATION .............................................................................................. 10

MATERIAL AND METHODS .......................................................................................................... 11

Study I .................................................................................................................................. 14Study II ................................................................................................................................ 14S tu d ie s I I I and IV ........................................................................................................ 15Study V .................................................................................................................................. 16S t a t i s t i c a l methods ..................................................................................................... 17

RESULTS ............................................................................... 17

F a m il ia l o ccurrence o f AAAs ( I ) ........................................................................ 17AAAs and ICAs ( I ) .......................................................................................................... 19L ip id s and l i p o p r o t e i n s ( I I ) ................................................................................ 21G enetic markers - HLA a n t ig e n s and blood groups ( I I I ) .................... 23G enet ic markers - serum p r o t e in groups (IV) ........................................... 25Aneurysm w a l l s - morphology (V) ........................................................................ 25

DISCUSSION .................................................................................................................................. 27

F a m il ia l occurrence o f AAAs ( I ) ........................................................................ 27L ip id s and l i p o p r o t e i n s ( I I ) ............................................................................... 31G enet ic markers ( I I I and IV) ................................................................................ 31Aneurysm w a l l s - morphology (V) ........................................................................ 33

CONCLUSION .................................................................................................................................. 34

ACKNOWLEDGEMENTS .................................................................................................................... 36

REFERENCES .................................................................................................................................. 37

Study I ................................................................................................................................... 43Study II ................................................................................................................................... 51Study II I ................................................................................................................................... 66Study IV ................................................................................................................................... 72Study V ................................................................................................................................... 77

7

INTRODUCTION

A r t e r ia l aneurysms were d e sc r ib e d a lrea d y in th e Eber Papurys in 1550

B.C. ( 1 ) . In the second c e n tu ry A .D . , Galen d e sc r ib e d an aneurysm as "a

p u l s a t i ve s w e l l i n g , from which b r ig h t blood spurted w ith g r e a t v i o l e n c e

i f i t was wounded" ( 2 ) . A n t y l l u s , in the same c e n tu r y , d i s t i n g u i s h e d

between tr u e and f a l s e aneurysms. He wrote: "There are two k inds o f an­

eurysms, the one where th e r e i s a l o c a l d i l a t a t i o n o f the a r t e r y , and

the o th e r from a rupture o f the a r t e r y and d is c h a r g e o f b lood to the

f l e s h beneath i t . Aneurysms due to d i l a t a t i o n are lo n g e r than the

o t h e r s . Those due to rupture are rounder" ( 3 ) . According to A et iu s o f

Ami da, in the 6 th cen tu ry A .D . , th e most common l o c a l i z a t i o n o f aneu­

rysms was on the neck, but aneurysms o f the b rach ia l a r t e r y caused by

u n s k i l l e d phlebotomy were a l s o common ( 3 ) . In 1567, V e s a l iu s o f

B r u s s e l s d e sc r ib e d an abdominal a o r t i c aneurysm (AAA), and in the same

c en tu ry Ambroise Pare s u g g e s t e d , t h a t aneurysms could be caused by lu e s

( 3 ) .

A lready in G a len 's and A n t y l lu s ' d ays , f a l s e aneurysms on the e x tr e m i­

t i e s had been t r e a t e d by l i g a t i o n o f the a r t e r y ( 3 ) . The f i r s t op era ­

t io n on the aorta was performed by S ir A s t l e y Cooper in 1817, when he

l i g a t e d the abdominal aorta o f a p a t i e n t with a l e a k in g aneurysm o f the

i l i a c a r t e r y (4 , 5 ) . However, the p a t i e n t d ied p o s t o p e r a t i v e l y . The

f i r s t s u c c e s s f u l l i g a t i o n o f the abdominal aorta was performed by

Rudolph Matas in 1923 ( 4 - 6 ) . His p a t i e n t had an AAA. During the f o l l o w ­

ing y e a r s a few p a t i e n t s with AAAs were op erated on by l i g a t i o n o f the

abdominal a o r t a , or by a l t e r n a t i v e methods such as wrapping and w ir in g ,

but the r e s u l t s were very d i s c o u r a g in g (4 , 5 , 7 ) . However, a new era in

the treatm ent o f AAAs s t a r t e d a f t e r 1951, when Dubost performed the

f i r s t s u c c e s s fu l r e s e c t i o n o f an AAA w ith r e s t i t u t i o n o f the c o n t i n u i t y

through a homologous g r a f t ( 8 ) . Within a s h o r t period o f t im e , o t h e r s

had s u c c e s s f u l l y performed the same type o f o p e r a t io n , and w i th in a few

y e a r s s y n t h e t i c g r a f t s had rep la ced the homografts in t h i s type o f op­

e r a t io n ( 9 - 1 1 ) .

The o p e r a t iv e m o r ta l i t y a t e l e c t i v e o p e r a t io n s o f AAAs has p r o g r e s s i v e ­

l y decreased during the p a st 30 y e a r s , and now v a r i e s between 1% and

10% in d i f f e r e n t s t u d i e s , w h i le the o p e r a t iv e m o r t a l i t y a t emergency

8

o p e r a t io n s s t i l l i s about 40% ( 1 2 - 1 5 ) . The rea l m o r t a l i t y in ruptured

AAAs i s h ig h e r , because some o f t h e s e p a t i e n t s d ie b e fo re the y come to

th e o p e r a t in g t h e a t r e .

The number o f e l e c t i v e o p e r a t io n s fo r AAAs has i n c r e a s e d , and t h i s de­

pends upon the good r e s u l t s a t e l e c t i v e o p e r a t io n s and the high r i s k

t h a t AAAs w i l l rupture ( 1 2 , 16 , 1 7 ) . However, the rea l frequency o f

AAAs in i n d u s t r i a l c o u n tr i e s has probably a l s o in c r e a s e d during t h i s

c e n tu r y . According to Kampmeier in a study from 1936, o n ly 313 AAAs had

been rep orted in the l i t e r a t u r e , and he added 68 c a s e s found among the

2 1 5 ,516 p a t i e n t s adm itted to the C harity H osp ita l during a 3 0 -y ea r

p er io d ( 1 8 ) . In autopsy s t u d i e s from the same per iod the frequency o f

p a t i e n t s with AAAs v a r ie d between 0.2% and 0.5%, w h i le in autopsy s t u ­

d i e s from the 1960s and the 1970s th e frequency v a r ie d between 1% and

6% ( 1 8 - 2 3 ) . However, many o f the AAAs found in the autopsy s t u d i e s were

s m a l l , and the m a jo r i ty o f them had not been d iagnosed c l i n i c a l l y and

had not ruptured.

Not o n ly the frequency but a l s o the e t i o l o g y o f AAAs has changed during

t h i s c e n tu r y . In the g r e a t m a jo r i ty o f the s t u d i e s performed b e fore

1950 n e a r ly a l l the AAAs were c o n s id e r e d to be caused by l u e s , w h i le in

l a t e r s t u d i e s n e a r ly a l l o f them were co n s id e r e d to be caused by a t h e r ­

o s c l e r o s i s ( 1 8 - 2 4 ) . However, i t has been p o in ted out th a t the change in

e t i o l o g y was very abrupt, and t h a t some o f the AAAs in the e a r l i e r s t u ­

d i e s probably were caused by a t h e r o s c l e r o s i s i n s t e a d o f lu e s ( 1 9 ) .

I t i s not known, why o n ly a small f r a c t io n o f a l l the i n d i v id u a l s with

a t h e r o s c l e r o s i s o f the abdominal aorta d eve lops AAAs, and why another

small f r a c t io n d eve lop s luminal o c c lu s io n o f the abdominal aorta ra th er

than an aneurysm (2 5 , 2 6 ) . I t has been s u g g e s te d , th a t o ther f a c t o r s

than a t h e r o s c l e r o s i s a l s o c o n t r ib u t e to the development o f a t h e r o s c l e ­

r o t i c AAAs ( 2 7 - 2 9 ) .

Mycotic AAAs and AAAs caused by n o n in f e c t io u s a r t e r i t i s are uncommon in

western c o u n tr i e s today (3 0 , 3 1 ) . AAAs have a l s o been reported in a few

p a t i e n t s with rare h e r e d i t a r y c o n n e c t iv e t i s s u e d i s o r d e r s , such as Mar­

fan ' s and E h le r s -D a n lo s ' syndromes (3 2 , 3 3 ) .

9

In the p r e s e n t i n v e s t i g a t i o n we have s tu d ie d the frequency o f f a m i l i a l

ag g r e g a t io n o f a t h e r o s c l e r o t i c AAAs, and the p a tte r n o f th e f a m i l i a l

ag g r e g a t io n o f AAAs. The o n ly r e p o r t on t h i s s u b j e c t t h a t we had found

in the l i t e r a t u r e was a c a s e r e p o r t from Great B r i t a in p re s e n te d by

C l i f t o n in 1977 ( 3 4 ) . He wrote about a f a m i ly , in which a l l the th r e e

c h i ld r e n had d eve loped a t h e r o s c l e r o t i c AAAs when th e y were between 60

and 70 y e a r s o l d . A ll o f them were men, and th e r e were no h i s t o r y o f

h e r e d i t a r y c o n n e c t iv e t i s s u e d i s o r d e r s in t h e i r fa m i ly .

Concerning f a m i l i a l a g g r e g a t io n o f n o n - a t h e r o s c l e r o t i c AAAs, Massumi e t

al rep orted in 1967 about two t w in s , a man and a woman, w ith Mar f a n ' s

syndrome, who had c l i n i c a l l y d iagnosed AAAs ( 3 5 ) . However, both o f them

d ied in ruptured t h o r a c i c a o r t i c aneurysms. The fem ale twin d ied a t th e

age o f 35 during pregnancy, and the male twin d ied a t the age o f 30 .

The i n f l u e n c e o f h e r e d i t a r y f a c t o r s f o r the development o f AAAs was

a l s o s tu d ie d by u s . P a t i e n t s w ith AAAs were s t u d ie d con cern in g the

serum c o n c e n t r a t io n s o f l i p i d s and l i p o p r o t e i n s and con cern in g the

d i s t r i b u t i o n s o f some g e n e t i c markers.

The serum c o n c e n t r a t io n s o f l i p i d s and l i p o p r o t e i n s are o f i n t e r e s t be­

cause a t h e r o s c l e r o s i s i s probably in v o lv e d in the development o f AAAs

(2 1 , 22 , 2 4 - 2 8 ) . In a t h e r o s c l e r o t i c d i s e a s e s o f the coronary a r t e r i e s

i t has been shown t h a t im portant r i s k f a c t o r s are high serum c o n c e n tr a ­

t i o n s o f t o t a l c h o l e s t e r o l and L D L -c h o le s t e r o l , and a low serum concen­

t r a t i o n o f HDL-cholesterol ( 3 6 , 3 7 ) . These serum c o n c e n t r a t io n s are to

some e x t e n t g e n e t i c a l l y determ ined , and t h i s may p a r t l y e x p la in the

p r e d i s p o s i t i o n to coronary a r t e r y d i s e a s e in some f a m i l i e s ( 3 8 - 4 0 ) .

Concerning p a t i e n t s w ith AAAs, we had found o n ly two s t u d i e s in which

the serum c o n c e n t r a t io n s o f t r i g l y c e r i d e and c h o l e s t e r o l were rep or ted

(4 1 , 4 2 ) . In one o f them both the serum c o n c e n t r a t io n s o f t r i g l y c e r i d e

and t o t a l c h o l e s t e r o l were h ig h er in th e p a t i e n t s than in the c o n t r o l s

( 4 1 ) . In the same study h y p e r l ip o p r o te in a e m ia acco rd in g t o Fredrickson

was r e p o r te d , and 36% o f the p a t i e n t s had abnormal l i p o p r o t e i n p a t ­

t e r n s .

The s tu d ie d g e n e t i c markers were HLA a n t i g e n s , the blood group system s

ABO, Rh, MNSs, P, K e l l , L e w is , and D u ffy , and the serum p r o te in group

10

system s h a p to g lo b in (Hp), t r a n s f e r r i n ( T f ) , g r o u p - s p e c i f i c component

(G c) , complement C3, properdin f a c t o r ( B f ) , and a l p h a - l - a n t i t r y p s i n

( P i ) .

Concerning t h e s e markers t h e r e are very few s t u d i e s in p a t i e n t s with

AAAs. There are fo ur s t u d i e s about ABO blood groups (4 3 -4 6 ) and one

study about Rh blood groups ( 4 7 ) . In one o f the s t u d i e s c o n cern in g ABO

blood groups a s i g n i f i c a n t i n c r e a s e o f b lood group A was found ( 4 5 ) ,

and in the study con cern in g Rh blood groups a s i g n i f i c a n t i n c r e a s e o f

R h -n e g a t ive i n d i v id u a l s was found ( 4 7 ) .

In the p r e s e n t i n v e s t i g a t i o n the morphology o f th e aneurysm w a l l s o f

p a t i e n t s with and w ith o u t AAAs in the fa m ily was a l s o s t u d ie d . The mor­

phology s t u d ie d by c o n v en t io n a l h i s t o l o g y has been d e sc r ib e d in o the r

s t u d i e s (2 6 -2 8 , 4 8 ) . S in ce c o l la g e n i s a major s t r e n g th e n in g component

o f the wall o f the abdominal aorta (2 9 , 4 8 , 4 9 ) , and i t has been r e ­

p orted t h a t some p a t i e n t s w ith in c r a c r a n ia l aneurysms are d e f i c i e n t in

c o l l a g e n ty pe III ( 5 0 ) , we a l s o s t u d ie d the o ccurrence o f c o l la g e n

ty p e s I and II I in the aneurysm w a l l s . We a l s o compared the smooth mus­

c l e c e l l s o f the abdominal aorta in i n d i v id u a l s with and w itho u t AAAs,

and in p a t i e n t s with and w ith o u t AAAs in the fa m i ly . The reason was

t h a t the smooth muscle c e l l s are c o n s id e r e d to produce the s t r e n g th e n ­

in g components o f the a o r t i c wall ( 2 7 , 5 1 - 5 3 ) . The comparison o f the

a o r t i c smooth muscle c e l l s was performed by s tu d y in g the occurrence o f

vim entin and desmin in the in te r m e d ia te f i la m e n t components (5 4 , 5 5 ) .

I t has been rep orted t h a t on ly v i men t i n- conta i n i n g smooth muscle c e l l s

are p r e s e n t in e x p e r im e n ta l ly induced in t im ai th ic k e n in g in the r a t ,

w h i le both v im e n t in - and d e sm in -c o n ta in in g smooth muscle c e l l s are

p r e se n t in the normal a o r t i c in tim a o f the r a t ( 5 4 ) .

AIMS OF THE INVESTIGATION

The aims o f t h i s i n v e s t i g a t i o n were

- to e s t im a te how o f t e n p a t i e n t s w ith AAAs have blood r e l a t i v e s with

the same d i s e a s e , and to e s t im a te the frequency o f i n d i v id u a l s with

AAAs among the blood r e l a t i v e s o f p a t i e n t s with AAAs ( I ) ,

- t o study the p a ttern o f the f a m i l i a l a g g r e g a t io n o f AAAs ( I ) ,

11

- to compare the serum c o n c e n t r a t io n s o f l i p i d s and l i p o p r o t e i n s in pa­

t i e n t s with " fa m i l ia l" and "non- fa m i l i a i " AAAs and in h e a l th y con­

t r o l s ( I I ) ,

- to compare the d i s t r i b u t i o n s o f d i f f e r e n t g e n e t i c markers in p a t i e n t s

with " fa m i l ia l" and " n o n - f a m i l i a l " AAAs and in c o n t r o l s ( I I I , IV ),

- to study the morphology o f the aneurysm w a l l s w ith con v en t io n a l

h i s t o l o g y , enzyme h i s t o c h e m is t r y and immunohistochemistry with a n t i ­

b o d ies a g a in s t c o l la g e n ty pe s I and I I I , v im entin and desmin (V).

MATERIAL AND METHODS

This i n v e s t i g a t i o n comprised 220 p a t i e n t s with AAAs, t r e a t e d a t the

S u rg ica l C l i n i c , U n iv e r s i ty H osp ita l o f Umeå in the northern part o f

Sweden, during the y e a r s 1 9 6 5-82 . I t in c lu d e s a l l the p a t i e n t s t r e a t e d

during the y e a r s 1965-81 and 20 o f the p a t i e n t s t r e a t e d in 1982. How­

e v e r , th e r e were d i f f e r e n t numbers o f p a t i e n t s in the d i f f e r e n t s t u ­

d i e s , and the re were d i f f e r e n c e s between the p a t i e n t s in d i f f e r e n t s t u ­

d ie s con cern in g the mean age a t the t ime o f d ia g n o s i s and where the pa­

t i e n t s l i v e d . A summary o f the d i f f e r e n t groups o f p a t i e n t s i s g iven in

Table I .

In a l l there were 172 men and 48 women. The mean age o f the p a t i e n t s a t

the t im e o f d ia g n o s i s was 6 6 .9 y e a r s (SD + 8 . 8 y e a r s , range 44-90

y e a r s ) . S ix p a t i e n t s were younger than 50 y e a r s and 13 p a t i e n t s were

o ld e r than 80 y e a r s . The mean age o f the men was 66 .1 y e a r s (SD +_ 8 . 8

y e a r s ) and the mean age o f the women was 7 0 .2 y e a r s (SD ± 8 . 0 y e a r s ) .

This d i f f e r e n c e i s s t a t i s t i c a l l y s i g n i f i c a n t ( t 2 i g = 2 . 9 , p< 0 . 0 1 ) .

There were 127 e l e c t i v e c a s e s and 93 emergency c a s e s . Concerning the

emergency c a s e s , 30 aneurysms were l e a k in g and 63 had ruptured. The

rupture was r e t r o p e r i t o n e a l in 36 c a s e s and in t o the abdominal c a v i t y

in 27 c a s e s . In the g r e a t m a jo r i ty o f c a s e s the aneurysms had been

v i s u a l i z e d on roentgenograms o f the abdomen. Furthermore, the d ia g n o s i s

had been confirmed by aortography in a l l the e l e c t i v e c a s e s and in 37

emergency c a s e s . E l e c t i v e o p e r a t io n s had been performed in 87 c a s e s and

emergency o p e r a t io n s in 66 c a s e s . In 27 c a s e s , p a t i e n t s with ruptured

Tabl

e I.

Num

ber

of p

atie

nts

, me

an

age

at th

e tim

e of

di

agno

sis

and

home

co

unty

of

th

e pa

tien

ts

in th

e d

iffe

ren

t st

ud

ies.

12

I -P > O O Z -O

I c a> a>■p + j to 4->W o> XJ

a )sz4-> 1

CD+■> fOfö •* -

"Oa>C D 4 -<c o

toc <u•f—<0 E COai T- o

s : - p c

<uEo

-P <t E (O < (O Q - < 4 -

■pc4- aj O -r-

0 0 «d- CO CM o CO CD

00* 0 0 0 0 0 0 CD 0 0 LO

+ 1 + 1+1 + 1 + 1 + 1 + 1CD cr> c o CO CM CO CD

CO CO CTv CO to COCO c o c o CO c o CO c o

0 0 CD CO CO LO CMr-i CM CM 1-1

CM o to 0 0 CO o CMr - co CO CD CM

> > * r -a> 4-> to to> fö c CLP Cl X> T- x =33 c: <u oc o toCO X3 fö -P s_ 4 - E

<U O -o a > u to O toS- CO to c. c •1 - S- >>ai ■C CL fö "O -P CL) to s--p a; • r - O o <U 3•P o CL CL o o c i. <L>a> a> CD i— a> fö fO cr

— 1 c _ J r— < -o CD E 3 = fÖ

K-. 3 »—I

13

AAAs had d ied p r e o p e r a t i v e ly or a t the b eg in n in g o f the o p e r a t io n , but

the d ia g n o s i s o f t h e s e p a t i e n t s was confirmed a t a u top sy .

The p a t i e n t s came in 124 c a s e s from our own co u n ty , the county V ä s te r ­

b o tte n (p o p u la t io n 2 3 6 , 0 0 0 ) , in 59 c a s e s from the county o f Norrbotten

(p o p u la t io n 2 6 4 ,0 0 0 ) and in 37 c a s e s from the northern p a r t o f the

county o f V ä s te r n o r r land (p o p u la t io n 1 4 6 ,0 0 0 ) . P a t i e n t s had been r e f e r ­

red from a l l the 11 o the r h o s p i t a l s in the area o f the u n i v e r s i t y hos­

p i t a l . Concerning our own co u n ty , 8 7 /124 p a t i e n t s came from the primary

area o f the u n i v e r s i t y h o s p i t a l (p o p u la t io n 1 1 0 ,0 0 0 ) . The la r g e number

o f p a t i e n t s from the primary area o f the u n i v e r s i t y h o s p i t a l in r e l a ­

t i o n to the p o p u la t io n depends upon, t h a t many p a t i e n t s had been t r e a t ­

ed a t d i s t r i c t h o s p i t a l s and county h o s p i t a l s .

As i l l u s t r a t e d in Table I , th e r e are d i f f e r e n c e s between the p a t i e n t s

in the d i f f e r e n t s t u d i e s co n cern in g the mean age a t the t im e o f d iagno­

s i s and con cern in g home county o f the p a t i e n t s . The mean age o f the

p a t i e n t s in some o f the s t u d i e s was lower than the mean age o f the pa­

t i e n t s who were not in c lu d ed in the s tu d y . This depends on t h a t t h e s e

s t u d i e s were r e t r o s p e c t i ve c o n cern in g the p a t i e n t s t r e a t e d b e fo re 1982,

and many p a t i e n t s who were o ld when t h e i r aneurysms had been d iagnosed

had a lrea d y d ied when our s t u d i e s were performed. In s t u d i e s I I , III

and IV, the p rop ort ion o f p a t i e n t s from the county o f V ä s te r b o t te n was

hig h er than in the o the r s t u d i e s , because in the r e t r o s p e c t i ve group,

fo r p r a c t i c a l and economical re a s o n , we o n ly t r i e d t o ob ta in blood

samples from the p a t i e n t s from our own c o u n ty . However, co n cern in g the

p a t i e n t s with AAAs in the fa m i ly , we t r i e d to ob ta in blood samples from

a l l o f them i r r e s p e c t i v e o f where the y l i v e d . All the c o n t r o l s in s t u ­

d i e s II - IV came from our own co u n ty .

The p a t i e n t s who were t r e a t e d in 1982, and in c lu d ed in the i n v e s t i g a ­

t i o n , were in te r v ie w e d about the o ccurrence o f AAAs in t h e i r f a m i l i e s

when they a r r iv e d to the h o s p i t a l . All th e s e p a t i e n t s e x c e p t one had

been t r e a t e d e l e c t i v e l y .

14

Study I

The aims were to study the frequency o f f a m i l i a l o ccu rrence o f AAAs,

and the p a tte r n o f the f a m i l i a l a g g r e g a t io n o f AAAs.

The study was r e tro spe c t!* ve and comprised a l l the 200 p a t i e n t s with

AAAs t r e a t e d a t the c l i n i c during the y e a r s 1965-81 . However, o n ly 89

o f th e s e p a t i e n t s were s t i l l "alive when the study was performed. A

l e t t e r survey con cern in g the o ccu rrence o f AAAs in the fa m ily was con­

ducted among the p a t i e n t s who were s t i l l a l i v e , w h i le in for m at ion about

the f a m i l i e s o f the d eceased p a t i e n t s was o b ta in ed from the medical

r e c o r d s .

At the t im e o f d ia g n o s i s the mean age o f the p a t i e n t who were s t i l l

a l i v e was 6 3 .5 y e a r s (SD + 8 . 4 y e a r s ) , w h i l e the mean age o f the r e ­

maining p a t i e n t s was 6 9 .6 y e a r s (SD +_ 8 . 3 y e a r s ) . The d i f f e r e n c e i s

s t a t i s t i c a l l y s i g n i f i c a n t ( t ^ = 5 . 1 , p < 0 . 0 0 1 ) . In 115 c a s e s

( 5 7 .5 $ ) the p a t i e n t s came from the county o f V ä s te r b o t t e n .

Study II

The aim was to compare the serum c o n c e n t r a t io n s o f t r i g l y c e r i d e , t o t a l

c h o l e s t e r o l , (VLDL + VLD)-chole s t e r o ! and H D L-cholesterol in AAA-pa-

t i e n t s with and w ith o u t AAAs in the fa m ily and in h e a l th y c o n t r o l s .

This study comprised 51 p a t i e n t s , 38 men and 13 women, o f whom 37 had

been t r e a t e d b e fo r e 1982. T h e r e fo r e , th e mean age o f the p a t i e n t s was

lower than the mean age o f the r e s t o f th e p a t i e n t s a t the t im e o f d i ­

a g n o s i s ( 6 3 .6 +_ 8 .2 y e a r s and 6 8 .3 _+ 8 . 3 y e a r s r e s p e c t i v e l y , t ? lß

= 3 . 5 9 , p < 0 . 0 0 1 ) . In 34 c a s e s (66.7%) the p a t i e n t s came from the

county o f V ä s te r b o t t e n . Twelve p a t i e n t s had f i r s t degree r e l a t i v e s

( b r o t h e r s , s i s t e r s and/or p a r e n ts ) with AAAs, and s i x p a t i e n t s had

second d egree r e l a t i v e s ( c o u s in s or b r o th e r s and s i s t e r s o f the par­

e n t s ) with AAAs.

As c o n t r o l s se rved 51 o f the randomly s e l e c t e d p a r t i c i p a n t s in a popu­

l a t i o n study o f serum l i p i d s . They had been matched with our p a t i e n t s

con cern in g sex and ag e . However, th e r e were no i n d i v id u a l s in the

p o p u la t io n study o f the same age as the o l d e s t p a t i e n t s , and in t h e s e

c a s e s the o l d e s t a v a i l a b l e c o n t r o l s were s e l e c t e d . C onsequently , the

mean age o f the p a t i e n t s was h igh er than the mean age o f the c o n t r o l s

15

when the blood samples were o b ta in e d ( 6 6 .7 +_ 7 . 4 y e a r s and 6 3 .8 +_ 5 .5

y e a r s r e s p e c t i v e l y , t 10Q = 2 . 2 3 , p < 0 . 0 5 ) .

In the p a t i e n t s HDL-cholesterol was determined on serum samples a f t e r

p r e c i p i t a t i o n o f YLDL and LDL by heparin-manganese p r e c i p i t a t i o n , w h i le

in th e c o n t r o l s the p r e c i p i t a t i o n had been done a f t e r u l t r a c e n t r i f u g a l

removal o f VLDL. However, th e r e was an e x c e l l e n t agreement between the

two methods.

S tu d ie s III and IV

The aim was t o compare the d i s t r i b u t i o n s o f g e n e t i c markers in AAA-pa-

t i e n t s with the d i s t r i b u t i o n s in c o n t r o l s and, in some c a s e s , w ith the

ex p e c te d d i s t r i b u t i o n a cco rd in g to the Hardy-Weinberg law ( 5 6 ) . In

study I I I , the g e n e t i c markers s t u d ie d were HLA a n t ig e n s A and B and

the blood group system s ABO, Rh, MNSs, P, K e l l , Lewis and D u ffy , and in

study IV the serum p r o te in groups h a p to g lo b in (Hp), t r a n s f e r r i n ( T f ) ,

g r o u p - s p e c i f i c component (G c), complement C3, properdin f a c t o r (Bf) and

a l p h a - l - a n t i t r y p s i n (P i ) were s t u d ie d .

The f r e q u e n c ie s o f ABO and Rh blood groups were based upon the r o u t i n e ­

ly performed t y p in g s o f 117 p a t i e n t s , 93 men and 24 women. In 29 c a s e s

the p a t i e n t s had AAAs in t h e i r f a m i l i e s . However, in fo u r c a s e s two

b r o th e r s and s i s t e r s and in t h r e e c a s e s two c o u s in s with AAAs had been

ty p e d , and th e r e f o r e the 29 p a t i e n t s w ith AAAs in the fa m ily were o f 22

d i f f e r e n t f a m i l i e s .

Concerning the o th e r g e n e t i c markers, blood samples were o b ta in ed from

55 p a t i e n t s , 40 men and 15 women, o f whom 17 had blood r e l a t i v e s with

AAAs. The d i s e a s e d fa m ily member was in 11 c a s e s a f i r s t degree r e l ­

a t i v e and in s i x c a s e s a second degree r e l a t i v e . The blood samples had

in 41 c a s e s been o b ta in ed from p a t i e n t s who had been t r e a t e d b e fo re

1982, and t h e r e f o r e the mean age o f th e p a t i e n t s s t u d ie d was lower than

the mean age o f the remaining p a t i e n t s a t the t ime o f d ia g n o s i s (6 3 .3

+_ 8 . 3 y e a r s and 6 8 .4 +_ 8 . 3 y e a r s r e s p e c t i v e l y , ^218 ~ ^«9» P <

0 . 0 0 1 ) . The p a t i e n t s in 39 c a s e s (70.9%) came from the county o f

V ä s te r b o t t e n .

16

The ty p in g fo r HLA a n t ig e n s and blood groups was performed a t the Blood

Center in Umeå and the ty p in g fo r serum p r o te in groups a t the D epart­

ment o f Medical G e n e t ic s in Umeå.

S u b je c t s from the county o f V ä s te r b o t t e n , who had a lr e a d y been typed

fo r o the r reasons served as c o n t r o l s . In some c a s e s th e s e s u b j e c t s had

p a r t i c i p a t e d in o th e r s t u d i e s performed a t the Department o f Medical

G e n e t ic s in Umeå ( 5 7 - 6 0 ) , and in o th e r c a s e s ( i . e . B f , Gc, P i) the r e ­

s u l t s o f the t y p in g s were a v a i l a b l e a t the same i n s t i t u t i o n but not

p u b lis h ed y e t .

Study V

The aim o f t h i s study was to compare the aneurysm w a l l s o f p a t i e n t s

with and w ith o u t AAAs in the fa m ily co n cern in g morphology s tu d ie d by

c o n v en t io n a l h i s t o l o g y , enzyme h i s t o c h e m is t r y and immunohistochemistry

with a n t ib o d ie s a g a in s t c o l l a g e n ty p e s I and I I I , v im entin and desmin.

The study comprised 24 p a t i e n t s , 22 men and 2 women, o p erated on for

AAAs a t the S u rg ica l C l i n i c , U n iv e r s i t y H osp ita l o f Umeå during the

y e a r s 1981 and 1982. F iv e p a t i e n t s had blood r e l a t i v e s with AAAs, and

one p a t i e n t had both an AAA and an in t r a c r a n i a l aneurysm (ICA). Sub­

j e c t s w ithout a o r t i c d i s e a s e , who had been a u to p s ie d a t the S ta t e In­

s t i t u t e o f F o ren s ic M edicine in Umeå, se rv ed as c o n t r o l s .

A r in g o f the c ircu m fe ren ce a t the c r a n ia l border o f the aneurysm was

taken as a b iopsy during the o p e r a t i o n s , a n d ‘from the c o n t r o l s the c o r ­

responding p a r t o f the abdominal a or ta was taken a t a u to p sy . C ry o s ta t

s e c t i o n s from a l l the a o r t i c specimens were s t a in e d fo r co n v en t io n a l

h i s t o l o g y and enzyme h i s t o c h e m i s t r y , w h i le c r y o s t a t s e c t i o n s from ten

p a t i e n t s were s t a in e d for c o l la g e n ty p e s and c r y o s t a t s e c t i o n s from 12

p a t i e n t s fo r v im entin and desmin.

Concerning the c o l la g e n study two o f the p a t i e n t s with AAAs in the

fa m i ly and the p a t i e n t with both an AAA and an ICA were in c lu d e d , and

co n cern in g the v im entin and desmin s t u d i e s a l l f i v e p a t i e n t s with AAAs

in the fa m ily and the p a t i e n t with both an AAA and an ICA were in c l u d ­

ed .

17

S t a t i s t i c a l methods

S tu d e n t ' s t - t e s t was used t o t e s t the d i f f e r e n c e in ages between the

p a t i e n t s in d i f f e r e n t groups.

The c h i - s q u a r e t e s t was used to compare th e numbers o f p a t i e n t s and

c o n t r o l s in d i f f e r e n t a l t e r n a t i v e grou p s , and to compare th e observed

and the ex p ec ted numbers o f p a t i e n t s in a l t e r n a t i v e groups. Yates c o r ­

r e c t i o n fo r c o n t i n u i t y was used when the number o f p a t i e n t s was small

( 6 1 ) .

The e x p ec ted numbers o f p a t i e n t s w ith a l t e r n a t i v e p h en otyp es , f o r exam­

p le blood groups MM, MN and NN, was c a l c u l a t e d acco rd in g to the Hardy-

Weinberg law ( 5 6 ) . The gene f r e q u e n c ie s p and q o f the genes M and N in

t h i s example were c a l c u l a t e d from the observed numbers o f p a t i e n t s w ith

the a l t e r n a t i v e p h en otyp es , and t h e s e gene f r e q u e n c ie s were used to

c a l c u l a t e the e x p ec ted numbers o f p a t i e n t s w ith a l t e r n a t i v e phenotypes .

I f t h e r e are nj MM-individual s , n2 M N -indiv idua ls and n3 N N -indi-

v i d u a l s , the gene f r e q u e n c ie s p and q are:

2n. + n2p = --------------------------- and q = 1 - p .

2 (n 1 + n2 + n3 )

The e x p ec ted numbers o f i n d i v id u a l s w ith the a l t e r n a t i v e phenotypes

w i l l be: p2 ( nj + n2 + 0 3 ) M M -indiv iduals , 2pq(n i + n2 + n3 )

MN-indivi du a ls and q2 (nj + n2 + n3 ) N N - in d iv id u a ls .

The Mann-Whitney U - t e s t was used to t e s t the d i f f e r e n c e between two

groups co n cern in g the serum c o n c e n t r a t io n s o f l i p i d s and l i p o p r o t e i n s

in study II ( 6 2 ) .

Only t w o - t a i l e d t e s t s were used , and p -v a lu e s below 0 .0 5 were c o n s i d e r ­

ed to be s t a t i s t i c a l l y s i g n i f i c a n t .

RESULTS

F a m il ia l occurrence o f AAAs ( I )

A d e t a i l e d p r e s e n ta t io n o f the r e s u l t s co n cern in g the p a t i e n t s t r e a t e d

b e fo r e 1982 i s g iven in Study I . The r e s u l t s o f t h a t study are summar­

i z e d here and in a d d i t i o n , the r e s u l t s c o n cern in g the p a t i e n t s t r e a t e d

in 1982 are p r e s e n te d .

18

The l e t t e r s u r v e y . The q u e s t io n n a ir e was answered by 8 7 /8 9 p a t i e n t s .

S ix te e n p a t i e n t s responded, t h a t the y had blood r e l a t i v e s with AAAs,

but t h i s in form at ion was wrong in t h r e e c a s e s . In one c a s e a s i s t e r o f

the p a t i e n t had a t h o r a c ic a o r t i c aneurysm in s t e a d o f an AAA, and in

th e two o th e r c a s e s th e p a t i e n t ' s b lood r e l a t i v e s had no aneurysms a t

a l l . On the o the r hand, a t l e a s t t h r e e o f the p a t i e n t s who denied th a t

t h e r e were any AAAs in t h e i r f a m i l i e s had blood r e l a t i v e s w ith AAAs. In

t h e s e c a s e s we su sp e c te d t h a t we had ob ta in ed wrong in form at ion from

the p a t i e n t s , because th e y had the same surnames and came from the same

communities as t h r e e o th e r p a t i e n t s w ith AAAs, who had been t r e a t e d a t

our c l i n i c e a r l i e r .

Thus, a t l e a s t 16/87 p a t i e n t s (18%) had blood r e l a t i v e s w ith AAAs. In

14 f a m i l i e s th e r e was o n ly one blood r e l a t i v e with AAA, and in two

f a m i l i e s th e r e were two blood r e l a t i v e s w ith AAAs. In one o f t h e s e two

c a s e s both the p a t i e n t ' s f a th e r and one o f h i s two b r o th e r s had d ied o f

ruptured AAAs, and in the o th e r both a b ro ther and a s i s t e r o f the pa­

t i e n t ' s f a th e r had d ied o f ruptured AAAs.

Nine out o f 87 p a t i e n t s (10%) had f i r s t degree r e l a t i v e s w ith AAAs, and

7 /8 7 p a t i e n t s (8%) had second degree r e l a t i v e s with AAAs. In 9 /468

c a s e s (1.9%) the p a t i e n t s ' b r o th e r s and s i s t e r s were a f f e c t e d , and 7 /

204 or 3.4% o f the dead b r o th e r s and s i s t e r s had d ied o f ruptured AAAs.

Among the blood r e l a t i v e s 1 4 /1 8 (78%) o f the AAAs had ruptured , w h i le

on ly 92/200 (46%) o f the AAAs t r e a t e d a t our c l i n i c during the y e a r s

1965-81 had ruptured or were l e a k i n g .

In the 16 f a m i l i e s w ith more than one AAA, t h e r e were 34 s u b j e c t s with

AAAs, o f whom 28 were men and 6 were women. In the remaining f a m i l i e s ,

th e r e were 55 men and 16 women with AAAs. There was no d i f f e r e n c e be­

tween the two groups co n cern in g the p r o p o rt io n s o f men and women.

At the t ime o f d ia g n o s i s the mean age o f the 16 p a t i e n t s with AAAs in

the fa m ily was 6 4 .3 y e a r s (SO + 7 .8 y e a r s ) , w h i le the mean age o f the

remaining 71 p a t i e n t s was 6 3 .4 y e a r s (SD _+ 8 .6 y e a r s ) .

Concerning the 16 f a m i l i e s with more than one AAA, two came from

V it ta n g i and two from Ö vertorneå , which are very small communities in

19

the northern p a r t o f th e area served by th e u n i v e r s i t y h o s p i t a l . How­

e v e r , th e r e was no c o n s a n g u in i ty in th e s e or In the o th e r f a m i l l t i e s .

A more d e t a i l e d d e s c r i p t i o n o f where 216 o f the p a t i e n t s in the i n v e s t ­

i g a t io n came from i s g iven in F ig . I .

The d eceased p a t i e n t s . A ccording to th e medical reco r ds fo u r o f th e s e

111 p a t i e n t s , o f which two were s i s t e r s , had AAAs in the f a m i ly . How­

e v e r , th e r e were a t l e a s t seven o th e r p a t i e n t s with AAAs in the fa m i ly .

T his in for m at ion was ob ta in ed by mere ch an ce , because the p a t i e n t s were

o f the same f a m i l i e s as seven o f the p a t i e n t s who had answered the

q u e s t i o n n a ir e .

Each o f the e le v e n p a t i e n t s with AAAs in th e fa m ily had a t l e a s t one

blood r e l a t i v e with AAA. The d i s e a s e d fa m ily member was in e i g h t c a s e s

a f i r s t degree r e l a t i v e and in th r e e c a s e s a second degree r e l a t i v e .

The p a t i e n t s t r e a t e d in 1 9 8 2 . Twenty o f th e p a t i e n t s t r e a t e d in 1982

were in te r v ie w e d about the o ccu rrence o f AAAs in t h e i r f a m i l i e s , and

3 /2 0 p a t i e n t s had blood r e l a t i v e s w ith AAAs. The d i s e a s e d fa m ily member

was in one c a s e the p a t i e n t ' s mother, in one c a s e one o f the p a t i e n t ' s

two sons and in one c a s e a b ro the r o f the p a t i e n t . P ed ig r ees o f t h e s e

t h r e e new f a m i l i e s w ith more than one AAA are shown in F ig . I I .

The t o t a l number o f f a m i l i e s w ith more than one AAA in the d i f f e r e n t

p a r ts o f t h i s study was 2 2 . In 20 o f t h e s e f a m i l i e s th e r e were two i n ­

d i v i d u a l s with AAAs, and in two f a m i l i e s th e r e were t h r e e i n d i v id u a l s

with AAAs, i n c lu d in g the probands. The d i s e a s e d fa m ily member was in 15

f a m i l i e s a f i r s t degree r e l a t i v e and in 7 f a m i l i e s a second degree r e l ­

a t i v e . Concerning the 15 p a t i e n t s with AAAs among the f i r s t degree r e l ­

a t i v e s , 13 p a t i e n t s had b r o th e r s and s i s t e r s with AAAs, w h i le the pa­

t i e n t ' s f a th e r was a f f e c t e d in one c a s e and one o f the p a t i e n t ' s sons

in a n o th er . Concerning the seven p a t i e n t s w ith AAAs among the second

degree r e l a t i v e s , f i v e p a t i e n t s had c o u s in s w ith AAAs.

AAAs and ICAs ( I )

B efore the l e t t e r survey was conducted we a lr e a d y knew t h a t one o f our

p a t i e n t s had blood r e l a t i v e s w ith ICAs. T herefore the p a t i e n t s in the

l e t t e r survey were a l s o asked about the o ccu rrence o f ICAs in t h e i r

20

• AAA/ AAA, letter survey \ AAA, fam il ia l

XX'AV 0 - 4 in h a b ita n ts /k m

5 - 1 0 in h a b i ta n ts /k m ^

> 1 0 in h a b ita n ts /k m

F ig . I . Home communities o f 216 o f the A A A -patien ts . The map shows the

area served by th e u n i v e r s i t y h o s p i t a l in Umeå.

21

OyO ö o o ü üÉ Û Ù i ü û û

t

Ü ô “ û

Ô ô i û û Û □ Ù o Ü Ó 0 t

Fi g. I I . The f a m i l i e s o f the t h r e e p a t i e n t s with AAAs in the fa m i ly ,

who had been t r e a t e d in 1982 (square = male, c i r c l e = fe m a le ,

f a m i l i e s . At l e a s t 5 /87 o f the p a t i e n t s had blood r e l a t i v e s w ith ICAs.

In one c a s e both a brother and a s i s t e r o f the p a t i e n t had d ied o f rup­

tured ICAs, and a co u s in o f the same p a t i e n t had been operated on fo r

an AAA. In another c a s e a s i s t e r o f the p a t i e n t ' s mother had d ied o f a

ruptured ICA, and a brother o f the p a t i e n t had an AAA. Concerning the

remaining p a t i e n t s , two had a b ro ther with an ICA and one had a cou s in

with an ICA.

Furthermore, 2 /87 p a t i e n t s in the l e t t e r survey had ICAs t h e m s e lv e s .

One o f them had a lread y been o p erated on fo r an ICA when he was t r e a t e d

a t our c l i n i c , and the o the r p a t i e n t has r e c e n t l y d ied o f a ruptured

ICA. There were no AAAs or ICAs in the f a m i l i e s o f th e s e two p a t i e n t s .

L ip id s and l i p o p r o t e i n s ( I I )

The serum c o n c e n t r a t io n s o f l i p i d s and l i p o p r o t e i n s in p a t i e n t s and in

c o n t r o l s are p resen ted in d e t a i l in Table II o f Study I I , w h i l e the

proport ion o f tobacco smokers and the occurrence o f o th e r a t h e r o s c l e ­

r o t i c d i s e a s e s are g iven in Table I o f the same stu d y .

arrow under the symbol = proband, b lack symbol = AAA).

Concerning the smoking h a b i t s , 40/51 p a t i e n t s and 14/51 c o n t r o l s were

smokers. The d i f f e r e n c e i s s t a t i s t i c a l l y s i g n i f i c a n t (X^=26.6, 1 d . f . ,

p < 0 . 0 0 1 ) .

22

Twenty out o f 51 p a t i e n t s had coronary a r t e r y d i s e a s e , 8 /51 p a t i e n t s

s u f f e r e d from i n t e r m i t t e n t c l a u d i c a t i o n and 2/51 p a t i e n t s had had

t r a n s i e n t i schaem ic a t t a c k s . More than one o f t h e s e d i s e a s e s occurred

in some o f the p a t i e n t s , and the t o t a l number o f p a t i e n t s with a t l e a s t

one d i s e a s e was 2 5 /5 1 .

The serum c o n c e n tr a t io n o f t r i g l y c e r i d e was h igh er in the 38 male pa­

t i e n t s than in the 38 male c o n t r o l s (1 .6 1 + 0 .1 0 mmol/I and 1 .2 4 + 0 .1 0

m m ol/ l , r e s p e c t i v e l y , U = 722 , p < 0 . 0 1 ) , and a l s o in the 13 female pa­

t i e n t s compared to the 13 fem ale c o n t r o l s (1 .9 6 + 0 .2 9 mmol/I and 1 .2 6

+ 0 .1 2 mmol/1, r e s p e c t i v e l y , U = 39 , p < 0 . 0 5 ) .

Concerning the serum c o n c e n t r a t io n o f t o t a l c h o l e s t e r o l , th e re was no

s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e between the male p a t i e n t s and the

male c o n t r o l s or between the female p a t i e n t s and the female c o n t r o l s .

The serum c o n c e n tr a t io n o f H DL-cholesterol was lower in the male pa­

t i e n t s than in the male c o n t r o l s (1 .0 1 + 0 .0 4 mmol/I and 1 .6 0 + 0 .0 5

m m ol/ l , r e s p e c t i v e l y , U = 132 , p < 0 . 0 0 1 ) , and again in the female pa­

t i e n t s compared to the female c o n t r o l s ( 1 .2 2 + 0 .1 3 mmol/I and 1 .9 6 +_

0 .1 5 m m ol/ l , r e s p e c t i v e l y , U = 2 6 , p < 0 . 0 1 ) .

The serum c o n c e n tr a t io n o f (VLDL + L D L )-ch o les ter o l was h igher in the

male p a t i e n t s than in the male c o n t r o l s ( 6 .5 2 + 0 .3 5 mmol/I and 5 .2 3 +

0 .2 3 mmol/I, r e s p e c t i v e l y , U = 44 4 , p < 0 . 0 1 ) , and in the female pa­

t i e n t s compared to the female c o n t r o l s ( 6 .4 8 +_ 0 .4 7 mmol / I and 5 .2 0 +

0 .3 5 mmol/I, r e s p e c t i v e l y , U = 4 1 , p < 0 . 0 5 ) .

No s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e s were found between the pa­

t i e n t s with and th o s e w ith o u t AAAs in the fa m ily co n cern in g the serum

c o n c e n t r a t io n s o f l i p i d s and l i p o p r o t e i n s .

S ix te e n out o f 38 men and 9 /13 women had o the r a t h e r o s c l e r o t i c d i s ­

e a s e s . However, th e r e was no d i f f e r e n c e between the men with and tho se

w ith o u t o the r a t h e r o s c l e r o t i c d i s e a s e s , or between the women with and

th o s e w ithout o the r a t h e r o s c l e r o t i c d i s e a s e s , co n cern in g the serum con­

c e n t r a t io n s o f t r i g l y c e r i d e , t o t a l c h o l e s t e r o l , HDL-chol e s t e r o l and

(VLDL + LDL) - c h o l e s t e r o l .

23

G en et ic markers - HLA a n t ig e n s and blood groups ( I I I )

The r e s u l t s are p res en ted in d e t a i l in Study I I I .

HLA a n t i g e n s . A com plete ty p in g o f seven HLA-A a n t ig e n s and e le v e n

HLA-B a n t ig e n s was performed on 48 p a t i e n t s . No s t a t i s t i c a l l y s i g n i f i ­

can t d i f f e r e n c e s were found between the p a t i e n t s and the 368 c o n t r o l s

co n cern in g the f r e q u e n c ie s o f t h e s e a n t i g e n s .

ABO and Rh blood g ro u p s . The f r e q u e n c ie s o f ABO and Rh blood groups in

117 p a t i e n t s and in 5 9 ,862 c o n t r o l s were compared. The frequency o f

blood group A among the p a t i e n t s and the c o n t r o l s was 5 1 .3 and 44.2%

r e s p e c t i v e l y , but t h i s d i f f e r e n c e was not s t a t i s t i c a l l y s i g n i f i c a n t .

However, con cern in g Rh blood groups on ly 7.7% o f the p a t i e n t s compared

to 14.9% o f the c o n t r o l s were R h -n e g a t iv e (x2 = 4 . 7 9 , 1 d . f . , p <

0 . 0 5 ) . There were no s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e s between the

p a t i e n t s with and th o s e w ith o u t AAAs in the fa m ily c o n cern in g ABO and

Rh blood groups.

MNSs blood g ro u p s . MN and Ss are se p a r a te blood group sy s t e m s , but com­

b in a t io n s o f the two blood group system s are u s u a l ly i n h e r i t e d as u n i t s

( 6 3 ) . The f r e q u e n c ie s o f the MNSs blood groups in 54 p a t i e n t s and in

287 c o n t r o l s were compared.

Concerning the MN blood groups t h e r e was a s t a t i s t i c a l l y s i g n i f i c a n t

e x c e s s o f MN h e te r o z y g o te s among the p a t i e n t s compared with the ex p e c ­

ted number accord in g to the Hardy-Weinberg law ( 5 6 ) . The observed d i s ­

t r i b u t i o n was 16 M M-patients, 33 MN-patients and 5 N N -p a t ie n t s , w h i le

the ex p ec ted d i s t r i b u t i o n was 1 9 .4 M M -patients, 2 5 .9 MN-patients and

8 . 6 N N -patien ts (X^ = 4 . 0 8 , 1 d . f . , p < 0 . 0 5 ) . The f r e q u e n c ie s p and q

o f the M- and N-genes among the p a t i e n t s were 0 . 6 and 0 . 4 r e s p e c t i v e l y .

The departure from the Hardy-Weinberg e q u i l ib r iu m with an e x c e s s o f MN

h e t e r o z y g o te s was p a r t i c u l a r l y pronounced among the 25 i n d i v id u a l s who

were ss homozygous. The observed d i s t r i b u t i o n was 2 MM-patients, 19 MN-

p a t i e n t s and 4 N N -p a t ie n t s , w h i le the e x p ec ted d i s t r i b u t i o n was 5 .3 MM-

p a t i e n t s , 1 2 .4 MN-patients and 7 .3 N N -patien ts (X2 = 7 . 0 2 , 1 d . f . , p <

0 . 0 1 ) . 33 /54 p a t i e n t s (61.1%) and 137/287 c o n t r o l s (47.7%) were MN-

h e t e r o z y g o t e s , but t h i s d i f f e r e n c e was not s t a t i s t i c a l l y s i g n i f i c a n t .

24

However, th e MNss type was more common among the p a t i e n t s than among

the c o n t r o l s ( 1 9 /5 4 or 35.2% and 55 /287 or 19.2% r e s p e c t i v e l y , X2 =

6 . 8 7 , 1 d . f . , p < 0 . 0 1 ) . The f r e q u e n c ie s p and q o f the M- and N-genes

among the c o n t r o l s were 0 .5 8 and 0 . 4 2 , r e s p e c t i v e l y .

Concerning the 17 p a t i e n t s w ith f a m i l i a l AAAs, t h e r e was a l s o a s t a t i s ­

t i c a l l y s i g n i f i c a n t departure from the Hardy-Weinberg e q u i l ib r iu m with

an e x c e s s o f M N -hetero?ygotes . The observed d i s t r i b u t i o n was 2 MM-pa-

t i e n t s , 13 MN-patients and 2 N N -p a t ie n t s , w h i le the ex p ec ted d i s t r i b u ­

t i o n was 4 . 3 MM-patients, 8 . 5 MN-patients and 4 .3 N N -p atien ts (X2 =

4 . 7 6 , 1 d . f . , p < 0 . 0 5 ) . The gene f r e q u e n c ie s p and q were 0 . 5 . The

freuqency o f M N-heterozygotes among t h e s e p a t i e n t s was a l s o h igher than

among the c o n t r o l s (1 3 /1 7 or 76.5% and 137/287 or 47.7%, r e s p e c t i v e l y ,

X2 = 4 . 2 3 , 1 d . f . , p < 0 . 0 5 , Yates c o r r e c t i o n ) .

Concerning the Ss blood groups th e r e was no s t a t i s t i c a l l y s i g n i f i c a n t

d e v ia t io n from the Hardy-Weinberg e q u i l ib r iu m , and no s t a t i s t i c a l l y

s i g n i f i c a n t d i f f e r e n c e between the p a t i e n t s and the c o n t r o l s .

Kell blood g ro u p s . The d i s t r i b u t i o n s in 54 p a t i e n t s and in 2 ,1 6 4 con­

t r o l s were compared.

There was a h igh er frequency o f K e l l - p o s i t i v e i n d i v id u a l s among the

p a t i e n t s than among the c o n t r o l s ( 7 /5 4 or 13% and 8 3 /2 ,1 6 4 or 3.8%

r e s p e c t i v e l y , X2 = 8 . 8 2 , 1 d . f . , p < 0 .0 0 5 , Yates c o r r e c t i o n ) . However,

t h e r e was on ly one K e l l - p o s i t i v e in d iv id u a l among the 17 p a t i e n t s with

AAAs in the fa m i ly .

L e w is , Duffy and P blood g ro u p s . Concerning th e s e blood groups th e re

were no s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e s between the p a t i e n t s and

the c o n t r o l s .

The f r e q u e n c ie s o f the Lewis b lood groups among the 52 p a t i e n t s were

21.2% a+b- , 75% a"b+ and 3.8% a“b - , and

among the 265 c o n t r o l s 21.1% a+b“ , 67.2% a"b+ , 11.7% a“ b~.

Concerning the 17 p a t i e n t s w ith AAAs in the fa m ily th e r e were

3 a“b+ , 13 a~b+ and 1 a ~ b - .

25

The f r e q u e n c ie s o f the Duffy b lood groups were among the 52 p a t i e n t s

29.6% a+b_ , 37% a+b+ and 33.3% a”b+ , and among the 797 con­

t r o l s 18.2% a+b” , 49.9% a+b+ and 31.9% a"b+ .

Concerning the 17 p a t i e n t s w ith AAAs in the fa m ily t h e r e were

6 a+b~, 8 a+b+ and 3 a"b+ .

The f r e q u e n c ie s o f the P blood groups were among the 53 p a t i e n t s

69.8% Pi and 30.2% P2 , and among the 404 c o n t r o l s 76.2% Pi and

23.8% P2 .

Concerning the 17 p a t i e n t s w ith AAAs in the fa m ily t h e r e were 12 Pi

and 5 P2 .

G enet ic markers - serum p r o te in groups (IV)

Haptoglobin (Hp) gro u p s . The d i s t r i b u t i o n s o f the h ap tog lob in groups in

55 p a t i e n t s and in 2 ,297 c o n t r o l s are shown in Table I o f s tudy IV.

There was a s t a t i s t i c a l l y s i g n i f i c a n t e x c e s s o f Hp 2-1 h e t e r o z y g o te s

among the p a t i e n t s compared with the c o n t r o l s and compared with the e x ­

p ec ted number o f h e t e r o z y g o t e s a cco rd in g to the Hardy-Weinberg law

( 5 6 ) . The observed d i s t r i b u t i o n was 4 ty pe 1 - 1 , 36 type 2 -1 and 15 type

2 - 2 , w h i le the ex p ec ted d i s t r i b u t i o n was 8 . 8 type 1 - 1 , 2 6 .4 ty p e 2-1

and 1 9 .8 type 2 -2 (X2 = 7 . 2 7 , 1 d . f . , p < 0 . 0 1 ) . The f r e q u e n c ie s p and

q o f the genes Hpl and Hp2 were 0 . 4 and 0 . 6 , r e s p e c t i v e l y .

Concerning the 17 p a t i e n t s with AAAs in the fa m ily th e r e were 12 ty pe

2-1 and 5 type 2 - 2 , w h i le the ex p e c te d numbers were 2 .1 ty p e 1 - 1 , 7 .7

type 2 -1 and 7 .2 ty p e 2 - 2 . The d i f f e r e n c e was not s t a t i s t i c a l l y s i g n i ­

f i c a n t (X2 = 3 .3 4 1 , 1 d . f . , 0 .1 < p < 0 . 0 5 , Yates c o r r e c t i o n ) .

T r a n s fe r r in ( T f ) , group s p e c i f i c component (G c), complement C3, proper­

din f a c to r (Bf) and a l p h a - l - a n t i t r y p s i n ( P i ) . The r e s u l t s co n cern in g

th e s e serum p r o te in groups are p r e s e n te d in Table I o f Study IV. There

were no s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e s between the p a t i e n t s and

the c o n t r o l s con cern in g the d i s t r i b u t i o n s o f th e s e serum p r o te in

g ro u p s .

Aneurysm w a l l s - morphology (V)

Conventional h i s t o l o g y and enzyme h i s t o l o g y . There were c o n s id e r a b le

d i f f e r e n c e s between the a o r t i c specimens from d i f f e r e n t p a t i e n t s con-

26

c e r n în g the degrees o f i n t i m a i , medial and a d v e n t i t i a l c h an ges . The

in t im a was in most c a s e s th ic k e n e d with prominent a t h e r o s c l e r o t i c

p la q u e s , atheromas and u l c e r a t i o n s . Calcium d e p o s i t s and e lo n g a te d

narrow spaces which had harboured c h o l e s t e r o l c r y s t a l s were common. The

media was in most c a s e s th in n e r than normal, and th e l a m e l la r p a tte r n

was u s u a l ly more or l e s s d estro y ed w ith fragm enta t ion and se p a r a t io n o f

th e e l a s t i n f i b e r s , and in some c a s e s t h e r e were p r a c t i c a l l y no e l a s t i n

f i b e r s a t a l l . Concerning the a d v e n t i t i t a c o n n e c t iv e t i s s u e p r o l i f e r ­

a t io n was common, and in some c a s e s t h e r e was fo c a l round c e l l r e a c -

t i o n .

Long s le n d e r c e l l s were common in the th ic k e n e d intim a and such c e l l s

a l s o surrounded the a t h e r o s c l e r o t i c p la q u e s . They s t a i n e d both with

NADH-TR and ATPase. In the media t h e r e was in most c a s e s a d ecreased

number o f smooth m uscle c e l l s , which s t a i n e d w ith both NADH-TR and

APase. In the a d v e n t i t i a the smooth m uscle c e l l s o f the vasa vasorum

s t a i n e d both w ith NADH-TR and ATPase, w h i l e the lymphoid c e l l s s t a in e d

on ly with NADH-TR.

There were no s y s t e m a t ic d i f f e r e n c e s between the aneurysm w a l l s from

p a t i e n t s with AAAs in the fa m ily and th o s e w i th o u t .

Immunohistochemistry - c o l la g e n ty p e s I and I I I . The in t im a , th e media

and the a d v e n t i t i a o f a l l the aneurysm w a l l s s t a in e d both with a n t i ­

b o d ie s a g a i n s t c o l l a g e n ty pe s I and I I I . However, the s p e c i f i c s t a i n i n g

o f the media was in most c a s e s more or l e s s overshadowed by the s t r o n g ­

l y a u t o f l u o r e s c e n t e l a s t i n f i b r i l s . No d i f f e r e n c e s cou ld be dem onstrat­

ed between p a t i e n t s w ith and w ith o u t AAAs in the fa m ily con cern in g the

occu rre nc e o f c o l la g e n in the aneurysm w a l l s .

Immunohistochemistry - v im entin and desm in . In the normal c o n t r o l s

v im entin was p r e s e n t in the e n d o t h e l i a l , the s u b e n d o th e l ia l and the

medial c e l l s , w h i le desmin was p r e s e n t in on ly a few o f the subendo-

t h e l i a l c e l l s and in a few o f the c e l l s in the o u te r part o f the media.

All the c e l l s which c o n ta in e d desmin a l s o c o n ta in e d v im en tin . In the

a d v e n t i t i a the bundles o f smooth muscle c e l l s co n ta in e d desmin but not

v im e n t in , w h i le the c o n n e c t iv e t i s s u e c e l l s c o n ta in e d vim entin but not

desmin.

27

Concerning the aneurysm w a l l s the m a jo r i ty o f th e smooth muscle c e l l s

in the in t im a , the media and the a d v e n t i t i a co n ta in e d v im e n t in , w h i le

o n ly a small p o r t io n o f t h e s e c e l l s c o n ta in e d desmin. However, in the

a d v e n t i t i a t h e r e were bundles o f smooth muscle c e l l s which s t a in e d with

desmin but not with v im en t in .

The morphology o f the smooth m uscle c e l l s in the aneurysm w a l l s v a r ie d

g r e a t l y . In the media the c e l l s were very th in and e l o n g a t e d , w h i le

l a r g e c e l l s with a la r g e number o f a u t o f l u o r e s c e n t granulae occurred in

the in t im a .

No s y s t e m a t ic d i f f e r e n c e s could be demonstrated between the aneurysm

w a l l s o f p a t i e n t s with and th o s e w itho u t AAAs in the fa m i ly .

V im e n t in -c o n ta in in g c e l l s were more common than d e sm in -c o n ta in in g c e l l s

in both normal and aneurysm atic a o r t i c w a l l s . C e l l s which c o n ta in e d

o n ly desmin were lo c a t e d in bundles in the a d v e n t i t i a .

To our knowledge no o the r study has been p u b lis h ed co n cern in g in term ed­

i a t e f i la m e n t p r o t e in s in smooth m uscle c e l l s in human a t h e r o s c l e r o t i c

v e s s e l s .

DISCUSSION

F a m il ia l occurrence o f AAAs ( I )

In the l e t t e r survey th e r e were on ly two m is s in g c a s e s , and th e r e was

no reason to b e l i e v e t h a t the m is s in g c a s e s were b ia s e d . The mean age

o f the p a t i e n t s in the l e t t e r survey was somewhat lower than the mean

age o f the o the r p a t i e n t s with AAAs a t the t ime o f d i a g n o s i s . This may

p o s s i b l y r e s u l t in a s l i g h t o v e r e s t im a t io n o f the freguency o f AAAs in

the f a m i l i e s o f p a t i e n t s with AAAs. However, we have reason to su s p e c t

th a t not a l l the AAAs in the f a m i l i e s have been rep orted and th a t we

in s t e a d have underest im ated the freguency o f AAAs in t h e s e f a m i l i e s .

One reason for th e s e s u s p i c i o n s i s th a t in thr ee c a s e s we d i sc o v e r e d by

mere chance t h a t p a t i e n t s who had denied th a t the y had any blood r e l ­

a t i v e s with AAAs were in r e a l i t y o f the same f a m i l i e s as th r ee o the r

p a t i e n t s with AAAs, who had p r e v io u s ly been t r e a t e d a t our c l i n i c . An­

28

o th e r reason i s the h igh p rop ort ion ( 1 4 /1 8 ) o f ruptured AAAs among the

blood r e l a t i v e s , w h i l e o n ly 92 /200 o f the AAAs t r e a t e d a t our c l i n i c

during the same period were l e a k in g or had ruptured . E i th e r th e AAAs in

the f a m i l i e s have a h igh er tendency t o rupture than o th e r AAAs, or the

p a t i e n t s have o n ly heard about and rep o rted the dramatic ruptured AAAs

in t h e i r f a m i l i e s .

However, a t l e a s t 16 /87 or 18% o f the p a t i e n t s in the l e t t e r survey had

blood r e l a t i v e s with AAAs. In 9 /87 c a s e s (10%) AAAs occurred among

t h e i r b r o th e r s and s i s t e r s . The frequency o f AAAs among a l l the b ro th ­

e r s and s i s t e r s was 9 /4 6 8 (1 .9% ), and 7 /204 (3.4%) o f the dead b ro th e rs

and s i s t e r s had d ied o f ruptured AAAs.

The p rop ort ion o f the p a t i e n t s , who had b r o th e r s and s i s t e r s w ith AAAs,

seemed to be h igher than e x p e c te d , but i t was d i f f i c u l t t o ob ta in r e l i ­

a b le c o n t r o l s w ith which to compare our r e s u l t s . To e s t im a te how o f te n

i n d i v id u a l s w ith o u t AAAs have blood r e l a t i v e s w ith AAAs, we t r i e d to

conduct a l e t t e r survey among 89 randomly s e l e c t e d s u b j e c t s o f the same

se x and age and from the same communities as the p a t i e n t s . However,

o n ly 67 s u b j e c t s answered the q u e s t i o n n a ir e . The fa th e r o f one o f th e s e

responders had d ied o f a ruptured AAA.

The frequency o f AAAs, and e s p e c i a l l y o f ruptured AAAs, among the

b r o th e r s and s i s t e r s o f the p a t i e n t s was probably a l s o h igher than e x ­

p e c te d . However, the e x a c t frequency o f AAAs in the northern p a r t o f

Sweden i s not known. To e s t im a te t h i s freq u en cy , we t r i e d to ob ta in i n ­

formation about the number o f p a t i e n t s w ith AAAs, who had been t r e a t e d

at a l l the c l i n i c s o f su rgery and in te r n a l m edic ine in the area o f our

u n i v e r s i t y h o s p i t a l during a t e n -y e a r p e r io d , but the rep orted numbers

o f p a t i e n t s from c l i n i c s o f the same s i z e v a r ie d c o n s id e r a b ly , and

th e r e f o r e based upon our survey the in form at ion ob ta in ed was probably

not r e l i a b l e .

In autopsy s t u d i e s the frequency o f AAAs v a r ie d between 1% and 6%, but

many o f the aneurysms in th e s e s t u d i e s are s m a l l , and the m a jo r i ty o f

them have not been d iagnosed c l i n i c a l l y and have not ruptured ( 2 1 - 2 5 ) .

Other problems con cern in g the autopsy s t u d i e s a r e , t h a t the autopsy

p e r cen ta g e in some s t u d i e s i s low, and t h a t the frequency o f AAAs found

29

a t autopsy depends upon the number o f AAAs which have been d iagnosed

c l i n i c a l l y and operated on (2 1 , 2 2 ) .

However, in an autopsy study w ith a very high autopsy p e r c e n ta g e from

Malmö in the southern p art o f Sweden o n ly 2 4 /5 ,3 8 6 or 0.4% o f th e

a u to p s ie d p a t i e n t s had c l i n i c a l l y d iagnosed and/or ruptured t h o r a c ic or

abdominal a o r t i c aneurysms ( 2 1 ) , w h i le 1.9% o f the b r o th e r s and s i s t e r s

o f th e p a t i e n t s in the l e t t e r survey had c l i n i c a l l y d iagnosed and/or

ruptured AAAs. The a u to p s i e s had been performed during the y e a r s 1957-

6 1 , when very few p a t i e n t s w ith AAAs were op erated on, w h i l e the major­

i t y o f the AAAs among the b r o th e r s and s i s t e r s o f the p a t i e n t s in our

study had been d iagnosed in the 1 9 7 0 s . AAAs were s l i g h t l y more common

in the 1970s than in the 1 9 6 0 s , but t h i s can hard ly e x p la in the d i f f e r ­

e n c e .

In the l e t t e r survey 7 /204 or 3.4% o f the dead b r o th e r s and s i s t e r s had

died o f ruptured AAAs, w h i le in another autopsy study from Malmö, which

comprised the a u to p s i e s performed during th e y e a r s 1 9 5 7-71 , on ly 4 2 /

2 0 ,591 or 0.2% o f the a u to p s ie d p a t i e n t s had d ied o f ruptured a th e r o ­

s c l e r o t i c AAAs ( 3 0 ) . This d i f f e r e n c e cannot be e x p la in e d by th e f a c t o r s

which d i f f e r between our study and the autopsy s tu d y . Ruptured AAAs,

which cause the p a t i e n t s d e a th , are probably se v e r a l t im es as common

among the b r o th e r s and s i s t e r s o f p a t i e n t s w ith AAAs, as in the genera l

p o p u la t io n .

In the l i t e r a t u r e , we had not found any s t u d i e s a t a l l co n cern in g how

o f t e n p a t i e n t s with AAAs have blood r e l a t i v e s with the same d i s e a s e , or

co n cern in g the frequency o f AAAs among the b r o th e r s and s i s t e r s o f pa­

t i e n t s with AAAs. Concerning the p a tte r n o f the f a m i l i a l a g g r e g a t io n o f

AAAs, the m a jo r i ty o f the AAAs in our study occurred among the pa­

t i e n t s ' b ro th e rs and s i s t e r s , w h i l e o n ly a few AAAs occurred among

t h e i r c o u s in s in s p i t e o f the f a c t t h a t th e r e are probably se v e r a l

t im es as many c o u s in s as b r o th e r s and s i s t e r s . In the l e t t e r su r v e y ,

nine b ro th e rs and s i s t e r s but o n ly f i v e c o u s in s had AAAs, and in the

o th e r s i x f a m i l i e s w ith more than one AAA, fo u r b r o th e r s and s i s t e r s

but no c o u s in s had AAAs. The r e s u l t s i n d i c a t e t h a t t h e r e i s a p r e d i s ­

p o s i t i o n to the development o f AAAs among the p a t i e n t s ' b r o th e r s and

s i s t e r s , but not among t h e i r c o u s i n s .

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The t o t a l number o f b lood r e l a t i v e s w ith AAAs in our study was 2 4 , d i s ­

t r i b u t e d among 22 f a m i l i e s . In 20 f a m i l i e s th e r e was one blood r e l a t i v e

w ith AAA, and in 2 f a m i l i e s t h e r e were two blood r e l a t i v e s with AAAs.

There was no d i f f e r e n c e between the p a t i e n t s w ith and th o se w ithout

AAAs in the fa m ily e i t h e r co n c e r n in g the p roport ion between men and

women, or the mean age a t the t ime o f d i a g n o s i s . These r e s u l t s i n d i c a t e

t h a t th e r e i s a general p r e d i s p o s i t i o n to the development o f AAAs among

the b ro th e rs and s i s t e r s o f p a t i e n t s w ith AAAs, ra th e r than t h a t th e r e

i s a s p e c i f i c group o f " fa m i l ia l" AAAs with another e t i o l o g y than the

o t h e r s .

As a lr e a d y mentioned , a c a s e re p o r t co n cern in g f a m i l i a l o ccu rrence o f

AAAs was p res en ted by C l i f t o n in 1977 ( 3 4 ) . In 1984, two s t u d i e s by

T i l son e t al have been p u b lis h e d con cern in g f a m i l i a l occurrence o f AAAs

( 6 4 , 6 5 ) . They were based upon c a s e r e p o r t s from s e v e r a l d i f f e r e n t

c l i n i c s in the United S t a t e s , and the y comprised 50 f a m i l i e s with more

than one AAA among f i r s t degree r e l a t i v e s . In th r e e c a s e s i d e n t i c a l

tw ins were a f f e c t e d , and in one o f t h e s e c a s e s the mother o f the tw ins

was a l s o a f f e c t e d . The number o f a f f e c t e d i n d i v id u a l s in a fa m ily was

two in 23 c a s e s , t h r e e in 21 c a s e s , fo u r in 3 c a s e s , f i v e in 2 c a s e s

and s i x in 1 c a s e . All the a f f e c t e d blood r e l a t i v e s ex c e p t two were

f i r s t degree r e l a t i v e s . I n d iv id u a l s from th r ee g e n e r a t io n s were a f f e c ­

ted in 3 c a s e s and i n d i v id u a l s from two g e n e r a t io n s in 15 c a s e s . The

s t u d i e s by T il son e t al do not g i v e any in for m at ion about how common

f a m i l i a l occurrence o f AAAs i s or about the frequency o f AAAs among the

blood r e l a t i v e s o f p a t i e n t s with AAAs, but they do show t h a t th e re i s a

p r e d i s p o s i t i o n to the development o f AAAs in a t l e a s t some f a m i l i e s .

In our l e t t e r su rvey , 2 /87 AAA-patients had c l i n i c a l l y d iagnosed ICAs,

and 5/87 o the r p a t i e n t s had blood r e l a t i v e s with c l i n i c a l l y d iagnosed

ICAs. Thus, i t does not seem p ro b a b le , t h a t the o ccu rrence o f a l l th e s e

ICAs i s f o r t u i t o u s . S in ce ICAs are not u s u a l ly caused by a t h e r o s c l e r o ­

s i s ( 6 6 ) , th e r e are probably o the r f a c t o r s , which p r e d isp o s e to the

development o f both a t h e r o s c l e r o t i c and n o n - a t h e r o s c l e r o t i c aneurysms

in t h e se i n d i v id u a l s and in th e s e f a m i l i e s . In the l i t e r a t u r e , we have

o n ly found two c a s e r e p o r t s co n cern in g the occurrence o f both AAA and

ICA in th e same in d iv id u a l (6 7 , 6 8 ) . F a m il ia l occurrence o f ICAs i s

g e n e r a l l y accep ted (6 9 , 7 0 ) , and one o f the p a t i e n t s in our study had

both a bro ther and a s i s t e r with ICAs, and a c o u s in with an AAA.

31

L ip id s and l i p o p r o t e i n s ( I I )

In Study II we found, t h a t the p a t i e n t s w ith AAAs had s i g n i f i c a n t l y

h ig h er serum c o n c e n t r a t io n s o f t r i g l y c e r i d e and (VLDL + LDL) - c h o l e s t e r ­

ol , and a s i g n i f i c a n t l y lower serum c o n c e n t r a t io n o f H DL-cholesterol

than h e a l th y c o n t r o l s o f the same se x and a g e . There was no s t a t i s t i c ­

a l l y s i g n i f i c a n t d i f f e r e n c e between th e p a t i e n t s with AAAs in the fam i­

l y and th o s e w ith o u t co n cern in g t h e s e serum c o n c e n t r a t io n s . However, i f

th e same p a tte r n o f serum c o n c e n t r a t io n s o f l i p i d s and l i p o p r o t e i n s i s

common among the b r o th e r s and s i s t e r s o f the p a t i e n t s and i f t h i s p a t ­

tern p r e d is p o s e s t o the development o f AAAs, t h i s c o r r e l a t i o n cou ld

e x p la in the high frequency o f AAAs among th e b r o th e r s and s i s t e r s .

In the l i t e r a t u r e , we have o n ly found one study c o n cern in g the serum

c o n c e n t r a t io n s o f l i p i d s and l i p o p r o t e i n s in p a t i e n t s w ith AAAs. In

t h i s study both the serum c o n c e n t r a t io n s o f t r i g l y c e r i d e and t o t a l

c h o l e s t e r o l were h igh er in the p a t i e n t s than in the c o n t r o l s , w h i l e the

serum c o n c e n t r a t io n s o f (VLDL + L D L )-c h o le s te r o l and HDL-cholesterol

were not rep orted ( 4 1 ) .

In our study a high p ro p o rt io n o f th e p a t i e n t s (2 5 /5 1 ) had o c c l u s i v e

a t h e r o s c l e r o t i c d i s e a s e s , and many p a t i e n t s ( 4 0 /5 1 ) were smokers. This

i s in accordance with the r e s u l t s o f o th e r s t u d i e s (2 5 , 41 , 7 1 - 7 3 ) .

There were no s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e s between the pa­

t i e n t s with and th o s e w ith o u t AAAs in the fa m ily co n cern in g the smoking

h a b i t s or the o ccu rrence o f o c c l u s i v e a t h e r o s c l e r o t i c d i s e a s e s .

The la r g e number o f p a t i e n t s w ith o c c l u s i v e a t h e r o s c l e r o t i c d i s e a s e s in

Study II could o f co u rse e x p la in the d e v i a t io n s from the c o n t r o l s con­

c e r n in g the serum c o n c e n t r a t io n s o f l i p i d s and l i p o p r o t e i n s , but when

th e p a t i e n t s w ith and w ith o u t o c c l u s i v e a t h e r o s c l e r o t i c d i s e a s e s were

compared co n cern in g the serum c o n c e n t r a t io n s o f l i p i d s and l i p o p r o ­

t e i n s , th e re was no s i g n i f i c a n t d i f f e r e n c e between them.

G enet ic markers ( I I I and IV)

The o n ly s t u d i e s on A A A -p a tien ts , t h a t we have found in th e l i t e r a t u r e

c o n cern in g the g e n e t i c markers s tu d ie d here are fo u r s t u d i e s con cern in g

ABO blood groups (4 3 -4 6 ) and one study c o n cern in g Rh blood groups ( 4 7 ) .

32

Concerning ABO blood grou p s , a s i g n i f i c a n t l y In cr ea sed frequency o f

blood group A was found In one o f the s t u d i e s ( 4 5 ) , w h i le no s t a t i s t i c ­

a l l y s i g n i f i c a n t d i f f e r e n c e between the p a t i e n t s and the c o n t r o l s was

found In the o th e r th r e e s t u d i e s (4 3 , 44 , 46) or In our s tu d y . Thus,

acco rd in g to the a v a i l a b l e In fo rm a t io n , t h e r e Is no a s s o c i a t i o n between

ABO groups and AAAs.

Concerning Rh blood grou p s , Morris and Bouhoutsos found a s i g n i f i c a n t l y

in c r e a s e d frequency o f R h -n e g a t iv e AAA-patients ( 4 7 ) , w h i l e we found a

s i g n i f i c a n t l y d ecreased frequency o f R h -n e g a t iv e A A A -patien ts . Con­

s e q u e n t ly , acco rd in g to the a v a i l a b l e in fo r m a t io n , t h e r e i s probably no

a s s o c i a t i o n between Rh blood groups and AAAs.

Concerning the MNSs blood group sy s t e m s , we found a s i g n i f i c a n t l y i n ­

cr e a s e d frequency o f M N-heterozygotes among the AAA-patients compared

with the e x p ec ted frequency a c co rd in g to the Hardy-Weinberg law. This

was more pronounced among the i n d i v id u a l s w ith blood group ss than

among the i n d i v id u a l s w ith blood groups SS and S s . As a lr e a d y mention­

ed , MN and Ss are two blood group s y s t e m s , which are c l o s e l y l in k e d to

each o th e r and th e r e f o r e th e y are u s u a l l y i n h e r i t e d as u n i t s ( 6 3 ) . In

s p i t e o f t h i s l i n k a g e , th e r e was no a s s o c i a t i o n between the Ss blood

group system and AAA. Concerning the MN blood group system i t i s s u s ­

p ec ted t h a t i n d i v id u a l s w ith blood groups MM and MN are more p r o te c te d

than i n d i v id u a l s w ith blood group NN a g a in s t e x te r n a l f a c t o r s which

a f f e c t th e serum c o n c e n t r a t io n s o f t r i g l y c e r i d e and c h o l e s t e r o l (7 5 ,

7 6 ) , However, t h i s cannot e x p la in why, a cco rd in g to our s tu d y , MN-indi-

v i d u a l s have an in c r e a s e d r i s k o f d e v e lo p in g AAAs. In our i n v e s t i g a ­

t i o n , both the MN blood groups and the serum c o n c e n t r a t io n s o f l i p i d s

and l i p o p r o t e i n s have been s tu d ie d in 48 p a t i e n t s . There were no d i f ­

f e r e n c e s con cern in g the serum c o n c e n t r a t io n s o f t r i g l y c e r i d e , t o t a l

c h o l e s t e r o l , (VLDL + L D L )-ch o les ter o l and H DL-cholesterol between the

p a t i e n t s with blood groups MM, MN and NN. C onsequent ly , the a s s o c i a t i o n

between the MN blood group system and AAA in our study does not seem to

be mediated by the serum c o n c e n t r a t io n s o f l i p i d s and l i p o p r o t e i n s .

Concerning the Kell blood group sy s tem , we found a s i g n i f i c a n t l y i n ­

c r e a s e d frequency o f K e l l - p o s i t i ve i n d i v id u a l s among the p a t i e n t s com­

pared with the c o n t r o l s . Both the Kell blood groups and the serum con-

33

c e n t r a t io n s o f T i p i ds and l i p o p r o t e i n s had been determined in 48 pa­

t i e n t s , but th e r e was no d i f f e r e n c e between the s i x K e l l - p o s i t i v e pa­

t i e n t s and the 42 K e l l - n e g a t i v e p a t i e n t s con cern in g the serum concen­

t r a t i o n s o f the l i p i d s and l i p o p r o t e i n s s t u d ie d .

In Study IV, we found a s i g n i f i c a n t l y in c r e a s e d frequency o f i n d i v i d ­

u a l s with hap tog lob in 2-1 type among the p a t i e n t s compared with the

c o n t r o l s , and compared with the ex p ec ted frequency a cco rd in g to the

Hardy-Weinberg law. There was no d i f f e r e n c e between the p a t i e n t s with

the d i f f e r e n t hap tog lob in ty p e s con cern in g the serum c o n c e n t r a t io n s o f

l i p i d s and l i p o p r o t e i n s (based on 48 p a t i e n t s ) .

We have found two s t u d i e s con cern in g the d i s t r i b u t i o n o f h ap tog lob in

ty pe s in p a t i e n t s w ith myocardial i n f a r c t i o n s . In one o f them th e re was

no s i g n i f i c a n t d e v ia t io n co n cern in g h ap tog lob in types ( 7 7 ) , and in the

oth e r th e re was a decreased frequency o f p a t i e n t s with Hp 2-1 type

compared with the exp ec ted frequency a c co rd in g to the Hardy-Weinberg

law ( 7 8 ) . C onsequently , t h e r e i s probably not an in c r e a se d frequency o f

the Hp 2-1 type in a t h e r o s c l e r o s i s per s e .

S in ce no o the r s t u d i e s have been rep orted con cern in g MN and Kell blood

groups and hap tog lob in groups in p a t i e n t s with AAAs, we do not know i f

othe r p a t i e n t s with AAAs have the same p a tte r n as our p a t i e n t s co n cern ­

ing t h e s e g e n e t i c markers.

Aneurysm w a l l s - morphology (V)

The primary aim o f t h i s study was to compare the morphology o f the an­

eurysm w a l l s o f p a t i e n t s with and w ithou t AAAs in the f a m i ly . Another

aim was to examine the a o r t i c w a l l s f o r c l u e s to the p a th o g e n e s i s o f

AAAs. S in ce on ly a minor p or t io n o f the i n d i v id u a l s with a t h e r o s c l e r o ­

s i s o f the abdominal aorta d eve lop AAAs, i t i s rea so n a b le to b e l i e v e

t h a t the re are lo c a l f a c t o r s in the a o r t i c wall which p r e d isp o se to the

development o f AAAs. Major s t r e n g th e n in g components in the a o r t i c wall

are c o l la g e n type s I and III ( 4 9 ) . Collagen and o ther components in the

a o r t i c wall are co n s id e r e d to be produced by the smooth muscle c e l l s

( 2 7 , 5 1 - 5 3 ) . Therefore i t i s o f i n t e r e s t t o study both the occurrence

o f c o l la g e n type s I and III and the smooth muscle c e l l s in p a t i e n t s

with AAAs. The methods we employed in t h i s study were co n v en t io na l

34

h i s t o l o g y , enzyme h i s t o c h e m is t r y and immunohistochemistry with a n t i ­

b o d ies a g a i n s t c o l la g e n ty p e s I and II I and with a n t ib o d ie s a g a in s t

vim entin and desmin in the smooth muscle c e l l s .

With t h e s e methods we d id not f in d any d i f f e r e n c e s between the aneurysm

w a l l s o f p a t i e n t s with and w ithou t AAAs in the f a m i ly . From a morpho­

l o g i c a l p o in t o f v iew, th e r e does not seem to be any s p e c i f i c " f a m i l i ­

al" AAAs. This i s in agreement with the r e s u l t s o f our o th e r s t u d i e s

( I I - I V ) , where we cou ld not f in d any d i f f e r e n c e s between AAA-patients

with and w ith o u t AAAs in the fa m ily co n cern in g the serum c o n c e n t r a t io n s

o f l i p i d s and l i p o p r o t e i n s or co n cern in g the d i s t r i b u t i o n s o f d i f f e r e n t

g e n e t i c markers.

Both c o l la g e n type s I and I I I were p r e s e n t in a l l the a o r t i c spec im ens .

T h erefore a d e f i c i e n c y o f one o f the major c o l la g e n type s could not e x ­

p la in the development o f t h e s e AAAs. However, the method employed was

not q u a n t i t a t i v e and does not say a n y th in g about the q u a l i t y o f the

c o l l agen.

On the b a s i s o f v im entin and desmin, we were ab le to c h a r a c t e r i z e three

types o f smooth muscle c e l l s in the a o r t i c wall - c e l l s which c o n ta in

v im e n t in , c e l l s which c o n ta in desmin and c e l l s which c o n ta in both

v im entin and desmin.

CONCLUSIONS

The r e s u l t s o b ta in ed permit the f o l l o w in g c o n c lu s io n s :

- F a m il ia l occurrence o f AAAs i s common. In our study 18% o f the AAA-

p a t i e n t s had blood r e l a t i v e s with c l i n i c a l l y d iagnosed and/or ruptur­

ed AAAs, and o f the p a t i e n t s ' b r o th e r s and s i s t e r s 1.9% had c l i n i c a l ­

l y d iagnosed and/or ruptured AAAs.

- There i s u s u a l ly on ly one blood r e l a t i v e with AAA, and AAAs are more

common among the b r o th e r s and s i s t e r s than among the c o u s in s o f pa­

t i e n t s with AAAs.

- High serum c o n c e n t r a t io n s o f t r i g l y c e r i d e and (VLDL + L D L )-c h o le s te r -

ol and a low serum c o n c e n tr a t io n o f HDL-chol e s t e r o l are common among

p a t i e n t s with AAAs whether or not they have AAAs in the fa m i ly .

35

- There are h igh f r e q u e n c ie s o f i n d i v id u a l s with blood group MN, o f

K e l l - p o s i t i v e i n d i v id u a l s and o f i n d i v id u a l s with h a p to g lo b in type

2-1 among p a t i e n t s with AAAS whether or not they have AAAs in the

fa m i ly .

- Both c o l la g e n ty p e s I and I I I , and smooth muscle c e l l s c o n t a in in g

v im e n t in , desmin, or v im entin and desmin, are p res en t in the w a l l s o f

AAAs. There i s no d i f f e r e n c e between the aneurysm w a l l s o f p a t i e n t s

with and p a t i e n t s w itho u t AAAs in the fa m ily con cern in g the morpho-

l o g y .

36

ACKNOWLEDGEMENTS

This i n v e s t i g a t i o n was performed a t the Department o f Surgery, Medicine and Medical G e n e t ic s and a t the Blood C enter , U n iv e r s i ty H osp ita l o f Umeå, and a t the Department o f Anatomy, U n iv e r s i ty o f Umea in Umeå.

I wish to exp ress my s i n c e r e g r a t i t u d e to a l l the peop le who have h e lp ­ed me in t h i s work and e s p e c i a l l y to :Docent Karl Axel Ängquist a t the Department o f Surgery, who i n i t i a t e d t h i s s tudy and e s t a b l i s h e d c o n t a c t with e x p e r ts in d i f f e r n t f i e l d s . Docent 01ev Rais a t the Department o f Surgery, who i n i t i a l l y s t im u la te d my i n t e r e s t in v a sc u la r su r g e r y , and who made me i n t e r e s t e d in abdomi­nal a o r t i c aneurysms.Docent L ar s-E r ic Thornell and h i s s t a f f a t the Department o f Anatomy, who has helped me with the m orpholog ica l part o f t h i s s tu d y .Docent Owe Johnson a t the Department o f M edic ine , who in trodu ced me to the f i e l d o f l i p i d s and l i p o p r o t e i n s , and whose s t a f f a t the research la b o r a to r y performed the d e te r m in a t io n s o f H D L -c h o le s te r o l .P r o fe s s o r Lars Beckman a t the Department o f Medical G e n e t i c s , who i n ­troduced me to the f i e l d o f blood grops as g e n e t i c markers.P r o fe s so r Gunhild Beckman a t the Department o f Medical G e n e t i c s , who, to g e th e r with her s t a f f , performed the t y p in g s o f serum p r o te in groups. Docent Anders E r iksson a t the Department o f F o ren s ic M edic ine , who has taken part in the m orpholog ica l s t u d i e s .Dr. B e r t i l Cedergren a t the Blood Center and h is s t a f f , who performed the HLA and blood group t y p i n g s .Dr. N i l s Fröhlander a t the Department o f Medical G e n e t ic s fo r h is a c t i v e i n t e r e s t , and for c o -a u th o r s h ip in the f i e l d o f serum p r o te in g ro u p s .P r o fe s s o r Sven Dahlgren a t the Department o f Surgery for p ro v id in g working c o n d i t i o n s which made i t p o s s i b l e to perform t h i s i n v e s t i g a ­t i o n .B i r g i t t a E r iksson at the Department o f Surgery for p r a c t i c a l a s s i s t ­ance .Anita Westman a t the Department o f Surgery , who took ca re o f a l l the blood sam ples .Loi ornai Örnehult for the f i n a l la y out o f t h i s t h e s i s , and fo r e x c e l ­l e n t ty p in g o f two o f the m an u scr ip ts .Bror Berggren a t the Department o f Anatomy for e x c e l l e n t photographic work.Dr. Barbara Kay Grove a t the Department o f Anatomy for r e v i s i n g my Engl i s h .My c o l l e a g u e s and the s t a f f a t the Department o f Surgery fo r t h e i r su p p ort .

This work was supported by the Medical F a c u l t y , U n iv e r s i ty o f Umeå.

37

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