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UBC Theses and Dissertations

Coronary artery intimal hyperplasia Harmon, Thomas Peter 1966

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i CORONARY ARTERY INTIMAL HYPERPLASIA by THOMAS PETER HARMON B . S c , M.D., U n i v e r s i t y o f B r i t i s h Columbia, 1963 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n the department o f ANATOMY We accept t h i s as conforming t o the r e q u i r e d s t a n d a r d THE UNIVERSITY OF BRITISH COLUMBIA June, 1966 In p r e s e n t i n g t h i s t h e s i s in p a r t i a l f u l f i l m e n t of the requirements fo r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study . I f u r t h e r agree that permiss ion f o r ex  t e n s i v e copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head of my Depar tment : or by h i s r e p r e s e n t a t i v e ^ . It i s understood that copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n  c i a l gain s h a l l not be a l lowed wi thout my w r i t t e n p e r m i s s i o n . THOMAS PETER HARMON'M.D. ANATOMY Department of The U n i v e r s i t y of B r i t i s h Columbia Vancouver 8, Canada SEPTEMBER 1, 1966 Date i i ABSTRACT I n t i m a l h y p e r p l a s i a i n the p r o x i m a l p o r t i o n o f the r i g h t coronary a r t e r y was i n v e s t i g a t e d by u s i n g l o n g i t u d i n a l s e c t i o n s o f the a r t e r y , t o determine the amount o f i n t i m a l and medial t h i c k n e s s , and the amount o f d e v i a t i o n from the normal o f the i n t e r n a l e l a s t i c lamina. One hundred and one samples i n the 0-30 year age range were used and the r e s u l t s c o r r e l a t e d w i t h other known i n f o r m a t i o n about the i n d i v i d u a l s . F i n d i n g s : 1. I n t i m a l t h i c k n e s s i n c r e a s e s d i r e c t l y as age i n c r e a s e s . 2. There was a sex d i f f e r e n c e i n the 16-30 year age group (males g r e a t e r than females), but not under 15 y e a r s . 3. I n t i m a l t h i c k n e s s i n c r e a s e s s i g n i f i c a n t l y as the amount o f i n t e r n a l e l a s t i c lamina change i n c r e a s e s . 4. M e d i a l t h i c k n e s s i n c r e a s e s s i g n i f i c a n t l y w i t h i n c r e a s i n g age. ad 5. i n t i m a l t h i c k n e s s i n c r e a s e s s i g n i f i c a n t l y ^ m e d i a l t h i c k n e s s , h e a r t mass and body mass i n c r e a s e , and i n c r e a s e s a t a more r a p i d r a t e than any o f the t h r e e . 6. The amount o f e l a s t i c lamina change i n c r e a s e s s i g n i f i c a n t l y w i t h age o n l y between 1 and 30 y e a r s . These f i n d i n g s are c o r r e l a t e d w i t h the p o s s i b l e f a c t o r s i n the e t i o l o g y o f i n t i m a l h y p e r p l a s i a . Signed; i i i TABLE OF CONTENTS PAGE Abstract i i Table of contents i i i L i s t of tables i v L i s t of figures v Acknowledgement v i i Introduction and objective 1 Li t e r a t u r e D e f i n i t i o n of intimal hyperplasia 3 Normal coronary artery wall 3 Hyperplasia of coronary artery intima 5 Internal e l a s t i c lamina change 10 Mucopolysaccharide changes 13 L o c a l i z a t i o n of lesions 18 D e f i n i t i o n of terms 20 Past correlations of intimal hyperplasia 22 Theories of etiology of intimal hyperplasia 28 Present study Procedure 39 Results 47 Conclusions and discussion 78 Bibliography 84 i v LIST OF TABLES PAGE I. Ages of specimens used 40 I I . Causes of death i n the 101 patients 41 I I I . Causes of death i n the 0-1 year age group 42 IV. Data obtained from the 101 specimens 48 V. Comparison of in t i m a l hyperplasia i n three age groups 62 (sexes combined) VI. Comparison of intimal hyperplasia i n three age groups 62 (males) VII. Comparison of intimal hyperplasia i n three age groups 63 (females) VIII. Comparison of intimal hyperplasia i n males and females 63 IX. Comparison of the average % i n t e r n a l e l a s t i c lamina 69 change i n three age groups (sexes combined) X. Comparison 1of the sex differences i n the average i n t e r n a l e l a s t i c lamina change i n three age groups 70 LIST OF FIGURES PAGE 1. Method o f p r e p a r i n g t i s s u e f o r l o n g i t u d i n a l s e c t i o n i n g 44 2. Diagram o f l o n g i t u d i n a l s e c t i o n to show q u a n t i t a t i v e e v a l u a t i o n 46 3. Photograph o f i n t a c t i n t e r n a l e l a s t i c lamina and no i n t i m a l h y p e r p l a s i a - (H. & E.) 52 4. Photograph o f i n t a c t i n t e r n a l e l a s t i c lamina and no i n t i m a l h y p e r p l a s i a - (aldehyde f u c h s i n ) 52 5. Photograph o f minimal i n t e r n a l e l a s t i c lamina change and minimal i n t i m a l p r o l i f e r a t i o n - (aldehyde f u c h s i n ) 53 6. Photograph o f moderate i n t e r n a l e l a s t i c lamina change and moderate i n t i m a l p r o l i f e r a t i o n - (H. & E.) 55 7. Photograph o f moderate i n t e r n a l e l a s t i c lamina change and moderate i n t i m a l p r o l i f e r a t i o n - (aldehyde f u c h s i n ) 55 8. Photograph o f l a r g e amount o f i n t e r n a l e l a s t i c lamina change and a l a r g e amount o f i n t i m a l p r o l i f e r a t i o n (alehyde f u c h s i n ) 57 9. Photograph o f l a r g e amount o f i n t e r n a l e l a s t i c lamina change and a l a r g e amount o f i n t i m a l p r o l i f e r a t i o n (aldehyde f u c h s i n ) 57 10. Graph o f i n t i m a i n microns on age i n y e a r s ( a l l cases) 59 11. Graph o f i n t i m a i n microns on age i n y e a r s - ( n o n - c h r o n i c d i s e a s e ) 60 12. Graph o f i n t i m a as a % o f t o t a l w a l l t h i c k n e s s on age i n y e a r s 61 13. Graph o f i n t i m a i n microns on i n t e r n a l e l a s t i c lamina change, as a % o f the t o t a l ( a l l cases) 65 v i LIST OF FIGURES (Cont'd.) PAGE 14- Graph o f i n t i m a i n microns on i n t e r n a l e l a s t i c lamina 66 change, as a % o f the t o t a l - (non-chronic d i s e a s e ) 15. Graph o f i n t i m a , as a % o f the t o t a l w a l l t h i c k n e s s , on the i n t e r n a l e l a s t i c lamina change, as a % o f the t o t a l 67 16. Graph o f i n t e r n a l e l a s t i c lamina change, as a % o f t o t a l on age i n yearsg 68 17. Graph o f media i n microns on age i n y e a r s 71 18. Graph o f i n t i m a i n microns on media i n microns 72 19. Graph o f i n t i m a i n microns on h e a r t weight i n grams 74 20. Graph o f i n t i m a i n microns on body weight i n pounds 75 21. Graph o f i n t e r n a l e l a s t i c lamina change, as a % o f t o t a l body weight i n pounds 76 v i i ACKNOWLEDGEMENT I wish t o thank P r o f e s s o r P a r i s C o n s t a n t i n i d e s f o r h i s h e l p and advic e d u r i n g the course o f t h i s work. Mr. B. Cox, was r e s p o n s i b l e f o r the p r e p a r a t i o n o f the s e c t i o n s and the photographs. The a r t e r i e s were o b t a i n e d through the c o u r t e s y o f : Dr. C.J. Coady o f the Department o f Pathology at the Royal Columbian H o s p i t a l , New Westminster, Dr. C L . Dolman o f the Department o f Pathology a t the Vancouver General H o s p i t a l , Vancouver, Dr. T.R. Harmon o f the Department o f Pathology at the L i o n s Gate H o s p i t a l , North Vancouver, and the Vancouver C i t y Morgue, Dr. J.A. Sturdy o f the Department o f Pathology a t S a i n t P a u l ' s H o s p i t a l , Vancouver. INTRODUCTION AND OBJECTIVE In 1951, Duff and McMillan (39) expressed the view that the fact that a r t e r i o s c l e r o s i s has i t s inception i n childhood and i s almost invariably present after adolescence, at l e a s t i n some degree, indicates an inherent s u s c e p t i b i l i t y of the human species to a r t e r i o s c l e r o s i s developing under apparently normal conditions. The structure of the intima undergoes considerable change from infancy to adult age and i t i s the purpose of t h i s thesis to investigate the growth of the int i m a l layer of the coronary artery with the aim to determine i f i t i s a product of some postnatal factor, such as injury, or i f i t i s a part of normal p h y s i o l o g i c a l growth. The o r i g i n and evolution of the a r t e r i o s c l e r o t i c process are obscure and doubts can be entertained about a l l features of a r t e r i o s c l e r o s i s as to t h e i r s i g n i f i c a n c e i n terms of cause and eff e c t , but, the early s t r u c t u r a l a l t e r a t i o n s of such a chronic disease as a r t e r i o s c l e r o s i s are important for an evaluation of the histogenesis and possible pathogenesis of the process. In 1915, Klotz (81) issued a dictum on such studies: "A study of the e a r l i e s t stages of the lesions i n the tissues of man i s s t i l l the most secure upon which to base conclusions". This statement actually was a c r i t i c i s m of works who made fa u l t y conclusions regarding a r t e r i o s c l e r o s i s , based on an examination only of l a t e lesions. The intimal layer of the coronary a r t e r i e s has been found to be r e l a t i v e l y thicker than that of other vessels with areas - 2 - o f t h i c k e n i n g p r e s e n t even i n i n f a n c y , and which become more prominent w i t h i n c r e a s i n g age. These l e s i o n s show a c e r t a i n p a r a l l e l i s m t o the g r o s s f i n d i n g s i n a d u l t s . (40) The s i g n i f i c a n c e o f m i c r o s c o p i c f i n d i n g s i n the i n t i m a are c o n s i d e r e d by many t o be u n c e r t a i n as we s t i l l do not know why the p r o c e s s occurs, why c e r t a i n i n d i v i d u a l s g e t more c l i n i c a l d i s e a s e than o t h e r s , or why the p r o c e s s tends t o i n v o l v e c e r t a i n p a r t s o f the a r t e r i a l t r e e . However, h y p e r p l a s i a of the i n t i m a i s g e n e r a l l y regarded as an e a r l y n o n - l i p i d phase o f athero- g e n e s i s and t h e r e f o r e d e t a i l e d knowledge of the coronary a r t e r y throughout l i f e may open new l i n e s o f r e s e a r c h which may enable the developement o f measures t o p r e v e n t or a t l e a s t delay the end stages, even though some i n v e s t i g a t o r s (117) s t i l l c l a i m t h a t a t the p r e s e n t i t seems very u n l i k e l y t h a t we s h a l l d i s  cover a cure f o r a r t e r i o s c l e r o s i s or coronary a r t e r y d i s e a s e , s i n c e some p a r t o f the p r o c e s s i s i r r e v e r s i b l e . A p r o g r e s s i v e i n v e s t i g a t i o n o f coronary s c l e r o s i s u s i n g c l i n i c a l m a t e r i a l i s i m p o s s i b l e due t o the i n a c c e s s i b i l i t y o f the c o r o n a r i e s , t h e r e f o r e s t u d i e s must use animal experiments and post-mortem m a t e r i a l . To date, animal experiments are not adequate t o study the e a r l y changes because they do not e x a c t l y p a r a l l e l the human l e s i o n s . To i n v e s t i g a t e the p o s s i b l e causes o f i n t i m a l h y p e r p l a s i a , we s t u d i e d post-mortem samples from 101 random a u t o p s i e s i n the age range 0 - 3 0 y e a r s by making l o n g i t u d i n a l s e c t i o n s o f the p r o x i m a l p o r t i o n o f the r i g h t coronary a r t e r y . The f i n d i n g s from V t h e s e s e c t i o n s were c o r r e l a t e d w i t h other known i n f o r m a t i o n about the i n d i v i d u a l s . - 3 - Review o f L i t e r a t u r e on I n t i m a l H y p e r p l a s i a  D e f i n i t i o n o f i n t i m a l h y p e r p l a s i a The s u b e n d o t h e l i a l l a y e r , or i n t i m a , i s thought t o be the p r e c u r s o r s i t e o f l a t e r a r t e r i a l d i s e a s e , the e t i o l o g y o f which i s unknown, bu t i n f e r e n c e s have been drawn from s t u d i e s based c h i e f l y on m i c r o s c o p i c s t r u c t u r a l changes. I t i s a f i b r o - e l a s t i c t h i c k e n i n g l y i n g between the endothelium and i n t e r n a l e l a s t i c l a m e l l a (104). The i n t i m a i s fundamentally an area o f p r o l i f  e r a t i o n o f v a r i o u s components c o n s i s t i n g o f f i b r o b l a s t - l i k e c e l l s which are p r o b a b l y r e s p o n s i b l e f o r the d e p o s i t i o n o f a complex mixture o f c o l l a g e n bundles, a c i d mucopolysaccharides, p r o l i f e r a t i n g and degenerating e l a s t i c f i b r e s , and smooth muscle c e l l s (21). The v a r i o u s i n t i m a l components are a l l the elements needed f o r the c o n s t r u c t i o n o f a t i s s u e which resembles t h a t o f the subjacent v a s c u l a r w a l l . I t i s s u g g e s t i v e o f a r e p a r a t i v e t i s s u e aiming a t the f o r m a t i o n o f a new b l o o d v e s s e l w a l l (115) which i n a l l p r o b a b i l i t y s t a r t s as a compensatory mechanism i n response t o some i n j u r y (62). The Normal Coronary A r t e r y W a l l B e f o r e d i s c u s s i n g i n d e t a i l the i n t i m a l l a y e r o f the coronary a r t e r y i t i s necessary f i r s t t o d e f i n e what i s t o be accepted as the normal. That i s , i f the i n t i m a l h y p e r p l a s i a i s t o be c o n s i d e r e d abnormal then d e s c r i p t i o n s must procede from a b a s e l i n e - the normal w a l l o f the coronary a r t e r y . One o f the e a r l i e s t d e s c r i p t i o n s o f a s o - c a l l e d normal t u n i c a i n t i m a was by R i n d f l e i s c h , 1872, (127) "The t u n i c a i n t i m a e x h i b i t s s t r i a t e d l a m e l l a e o f Henle which are f i n e l y s t r i a t e d , wavy l a y e r s o f b a s i s - s u b s t a n c e (of c o n n e c t i v e t i s s u e ) , i n whose i n t e r s t i c e s f l a t t e n e d , l e n t i c u l a r c o r p u s c l e s are imbedded. I n these c e l l - c o n t a i n i n g spaces, the opposed s u r f a c e s o f the b a s i s - substance e x h i b i t s a p e c u l i a r homogeneous l u s t r e , morever, they p r e s e n t a double contour, which makes each c e l l appear as i f surrounded by a s p e c i a l c a p s u l e . The c e l l - c o n t a i n i n g spaces appear o f a s t e l l a t e form, w i t h b r a n c h i n g p r o l o n g a t i o n s which anastomose w i t h one another." From h i s d e s c r i p t i o n , he i s r e f e r r i n g t o a s u b e n d o t h e l i a l l a y e r w i t h the v a r i o u s components mentioned e a r l i e r a l r e a d y p r e s e n t . Even as r e c e n t l y as 1965, (52, 55, 86) some i n v e s t i g a t o r s r e g a r d the normal i n t i m a as a t h i c k e n e d l a y e r w i t h the l i n i n g endothelium, a l a y e r o f sub e n d o t h e l i a l c o n n e c t i v e t i s s u e , i n which t h e r e may be a few muscle f i b r e s , and an i n t e r n a l e l a s t i c membrane. These workers agree t h a t the i n t i m a undergoes p r o g r e s s i v e growth from an ex c e e d i n g l y t h i n s t r u c t u r e at b i r t h but c o n s i d e r t h i s s t i l l t he normal i n t i m a . (55) A more accepted c o n c e p t i o n o f the normal a r t e r i a l w a l l i s the p i c t u r e b e f o r e any h y p e r p l a s i a (1, 29, 40, 49, 61, 109, 117, 119), c o n s i s t i n g o f a s i n g l e l a y e r o f the e n d o t h e l i a l c e l l s with o n l y a few s t r a n d s o f c o l l a g e n between i t and an i n t a c t i n t e r n a l e l a s t i c membrane. (41, 97). Under the E l e c t r o n microscope, (119) the i n t i m a i s seen t o c o n s i s t mainly o f e n d o t h e l i a l c e l l s w i t h j u n c t i o n s r e s u l t i n g from o v e r l a p p i n g o f the c e l l margins which abut on the i n t e r n a l e l a s t i c lamina. The e n d o t h e l i a l c e l l s send f i l i f o r m p r o c e s s e s t o the media through the f e n e s t r a t i o n s , p o s s i b l y f o r n u t r i t i o n o f the media:., through the r e l a t i v e l y - 5 -' impermeable e l a s t i c membrane by the many caveolae i n t r a c e l l u l a r s and small v e s i c l e s of t h e i r cytoplasm. The normal i n t e r n a l ' e l a s t i c lamella i s seen to be a continuous fenestrated subendothelial tube of homogeneous r e f r a c t i l e material of moderate density, i n which numerous f i b r e s of 500A diameter with no p e r i o d i c i t y are imbedded (106). I t has an i r r e g u l a r surface and sends branches to the media between the smooth muscle layers (119). The longitudinal corru gations are due to post mortem muscular contraction (41). Osborn (1963) (117) claimed that i n 465 infants dying at b i r t h the coronary artery demonstrated t h i s normal appearance. Others (40, 61, 63, 88, 91, 103, 130, 131) have demonstrated deviations from the normal i n premature infants ( i . e . prenatally), and i n newborns. Hyperplasia of the coronary artery intima Intimal growth i s l a r g e l y a post natal process and contin ues, i n many cases, through l i f e and varies from i n d i v i d u a l to i n d i v i d u a l . Rokitansky, 1852, (136) was one of the f i r s t to describe the growth of the intima and regarded i t as a precursor of other conditions including the atheromatous process. He described i t as "an excessive formation and deposition of the l i n i n g membrane of;}the artery derived from the mass of the blood, and at the same time constitutes hypertrophy of t h i s membrane and, being s p l i t i nto lamellae, i s drawn away i n the form of strata, varying i n thickness". He found i t varied from a t h i n s o f t moist and succu lent nature i n the translucent or early lesions, to a thicker, dense, dryH, tough and e l a s t i c nature i n the older or opaque portions. He noted that i t varied i n extent from l o c a l patches to the whole - 6 - vessel, e s p e c i a l l y prominent at b i f u r c a t i o n of a vessel, and re garded the whole process as re l a t e d to a chronic inflammation. Virchow, 1856, (11, 56, 87, 128) also found that the e a r l i e s t changes i n a r t e r i o s c l e r o s i s occurred i n the intima and consisted of a gelatinous swelling i n t h i s layer with accumulation of material resembling mucus and d e l i c a t e e l a s t i c f i b r e s i n t h i s "structureless diaphanous i n t e r c e l l u l a r substance". Concomitant with t h i s a l t e r a t i o n he noted an enlargement and m u l t i p l i c a t i o n of the connective tissue c e l l s to form l o c a l i z e d thickening. This i s a si m i l a r picture to that which Rindfleisch described as a "normal intima". Since Virchow*s and Rokitansky's description of the intima the views have been changed and re f i n e d with the developement of the newer techniques. Intimal growth i s very si m i l a r to the reparative process of connective tissue following injury, with a r e l a t i v e l y orderly sequence of the various processes r e s u l t i n g i n the complex picture of the hypertrophied intima. (67, 106) The f i r s t demonstrable deviation from the normal wall i s a l t e r a t i o n of the i n t e r n a l e l a s t i c lamina which undergoes fraying, s p l i t t i n g , fragmentation and reduplication (29, 34, 40, 63, 88, 103, 105, 139, 148). There i s a s l i g h t disagreement as to the e a r l i e s t changes. There i s a question whether perhaps the i n i t i a l change i s characterized by several simultaneous alt e r a t i o n s i n  cluding the e l a s t i c changes, an increased production of acid muco polysaccharides at the s i t e of the e l a s t i c changes, and the appear ance of f i b r o b l a s t i c c e l l s i n the subendothelial area (55, 106, 107, 110, 117, 142). There i s general agreement, however, that these changes are a l l present early i n the process (29,40,41,49, - 7 - 51,88, 117, 125, 139,148). F o l l o w i n g the i n i t i a l change the processes can be d i v i d  ed i n t o the f o l l o w i n g components: (107) 1) p r o l i f e r a t i o n of f i b r o b l a s t i c c e l l s 2) d e p o s i t i o n o f i n c r e a s i n g amounts o f a c i d mucopolysaccharides 3) f u r t h e r d e g eneration o f e l a s t i c lamina 4) r e g e n e r a t i o n of new e l a s t i c t i s s u e 5) f o r m a t i o n o f c o l l a g e n f i b r e s 6) h y a l i n e degeneration o f c o n n e c t i v e t i s s u e o c c u r r i n g l a t e and p r o c e e d i n g t o f u r t h e r d e g e nerative l e s i o n s . I n e a r l y c h i l d h o o d the p r o c e s s b e g i n s f o c a l l y b ut eventu a l l y become d i f f u s e i n the sense t h a t most o f the i n t i m a l s u r f a c e i s i n v o l v e d , some areas t o a g r e a t e r degree than o t h e r s (35). The f o c i seen i n c h i l d h o o d are o f a c e l l u l a r nature e x h i b i  t i n g the e l a s t i c lamina changes, i n c r e a s e d mucopolysaccharides, and the i n t r u s i o n o f some muscle c e l l s between the gaps o f the i n t e r n a l e l a s t i c lamina. These c e l l s are a s s o c i a t e d w i t h the p r o d u c t i o n o f d e l i c a t e e l a s t i c f i b r e s and c o l l a g e n (29, 34, 131). The muscle c e l l s r e o r i e n t themselves t o form a l a y e r o f l o n g i t u d i n  a l smooth muscle i n s i d e the remnants o f the i n t e r n a l e l a s t i c lamina (34, 41, 64, 99, 105, 134). T h i s has been c a l l e d the musculo- e l a s t i c l a y e r (39, 40, 64, 93, 105). with advancing age t h e r e i s a p r o g r e s s i v e i n c r e a s e i n the above components w i t h a r e l a t i v e i n c r e a s e i n new e l a s t i c t i s s u e and more and more i n t e r c e l l u l a r c o n n e c t i v e t i s s u e elements, mainly c o l l a g e n (41, 64, 88, 93, 99, 105). with f u r t h e r p r o g r e s s i o n t h e r e i s complete d i s s o l u t i o n o f the remnants o f the i n t e r n a l e l a s t i c lamina and degeneration o f t e n o f some o f the new e l a s t i c t i s s u e r e s u l t i n g i n an i n d i s t i n c t - 8 - d i v i s i o n between media and i n t i m a , w i t h h y a l i n i z a t i o n of the con n e c t i v e t i s s u e elements and appearance o f l i p i d as d r o p l e t s , or foam c e l l s and e v e n t u a l l y as c h o l e s t e r o l c l e f t s (34,35,40, 105). In the p a s t the d i f f e r e n t stages i n t h i s continuous p r o c e s s have been segregated. F i r s t the "musculo e l a s t i c l a y e r " was mentioned. As the e l a s t i c components i n c r e a s e d mainly i n s i d e the l o n g i t u d i n a l muscle l a y e r an " e l a s t i c h y p e r p l a s t i c l a y e r " was d e f i n e d , and w i t h the d e p o s i t i o n o f l a r g e amounts o f c o l l a g e n e s p e c i a l l y on the i n n e r s u r f a c e ^ ' t h e c o n n e c t i v e t i s s u e l a y e r " was d e f i n e d (29, 40,41, 47, 64, 103, 112). Since these changes are phases o f continuous t i s s u e a l t e r a t i o n and s i n c e the l a y e r s depend upon the stage o f the l e s i o n when seen, i t i s unnecessary t o c o n t i n u e t o d e f i n e these l a y e r s . A l s o , s i n c e the changes are u s u a l l y uneven i n an a r t e r y , a l l these l a y e r s can occur a t one time (40, 64). The media under the i n t e r n a l e l a s t i c lamina may a l s o e x h i b i t a r e o r i e n t a t i o n o f bundles o f smooth muscle c e l l s i n a l o n g i t u d i n a l d i r e c t i o n p a r a l l e l t o those i n the i n t i m a , thus p r e s e n t i n g a d i f f i c u l t y i n d e f i n i n g media from the new t i s s u e or i n t i m a (47, 131). U n t i l r e c e n t l y t h e r e had been c o n f u s i o n as t o the type and o r i g i n o f the c e l l u l a r components of the i n t i m a . O r i g i n a l l y the c e l l s o f the i n t i m a were thought t o a r i s e from the c i r c u l a t i n g b l o o d (87) and l a t e r they were thought t o be f i b r o b l a s t s (106, 128) from t h e i r appearance and a l s o from the f a c t t h a t b e i n g almost the o n l y c e l l p r e s e n t i n the i n t i m a , they had t o be r e s p o n s i b l e f o r the p r o d u c t i o n o f new e l a s t i c f i b r e s , c o l l a g e n and mucopoly s a c c h a r i d e s . In o t h e r words, they were h e l d r e s p o n s i b l e f o r - 9 - p r o d u c i n g the e x t r a c e l l u l a r m a t e r i a l o f r e p a i r , (4, 21, 105,106, 128, 146, 155) and f o r p h a g o c y t o s i s (29, 34). With e l e c t r o n microscopy these c e l l s have been shown t o be i n i n t i m a t e a s s o c i a t i o n w i t h and to produce these e x t r a c e l l u l a r s t r u c t u r e s (27, 53, 56). w i t h l i g h t microscopy these c e l l s a l s o possessed the c h a r a c t e r i s t i c s o f smooth muscle c e l l s i n c l u d i n g the shape o f the c e l l and nucleus w i t h i t s coarse chromatin d i s t r i b u  t i o n , the e o s i n o p h i l i c s t a i n i n g q u a l i t i e s o f the cytoplasm, and the presence o f numerous f i b r i l s p a r a l l e l t o the long a x i s o f the c e l l . These f i b r i l s , o f which the coarse ones were s i t u a t e d a t the c e l l boundaries and the more d e l i c a t e ones i n the cytoplasm proper, were seen t o extend beyond the c e l l boundaries t o adjacent c e l l s , s t a i n e d i n t e n s e l y r e d w i t h Masson's t r i c h r o m e and gave a p o s i t i v e r e a c t i o n w i t h PTAH and t h e r e f o r e were c o n s i d e r e d t o be m y o f i b r i l s (56, 69, 112). The c e l l s a l s o have been claim e d t o possess the c a p a b i l i t y o f c o n t r a c t i l i t y (69). A l l these c h a r a c t e r i s t i c s suggest t h a t these are smooth muscle c e l l s and not f i b r o b l a s t s . (4, 99). With the e l e c t r o n microscope more evidence has been o b t a i n  ed to c o n f i r m t h e i r i d e n t i t y as smooth muscle c e l l s . Myofilaments s i m i l a r t o those o f o r d i n a r y smooth muscle, t h a t i s , of 50-100 A° diameter were seen massed t o g e t h e r and c o n f i n e d t o a t h i n l a y e r c l o s e t o the plasma membrane and other c y t o p l a s m i c o r g a n e l l e s i n  c l u d i n g apparatus f o r p r o t e i n s y n t h e s i s , were more wi d e l y s c a t t e r  ed i n the c e n t r a l cytoplasm (27, 28, 53, 56). There have been v a r i o u s t h e o r i e s as t o the o r i g i n o f these smooth muscle c e l l s i n c l u d i n g d e d i f f e r e n t i a t i o n from e n d o t h e l i a l c e l l s r e g e n e r a t i n g f o l l o w i n g damage (8, 6 9>) - 10 - or d i f f e r e n t i a t i o n from f i b r o b l a s t s (29). Another theory i s t h a t the smooth muscle c e l l s a r i s e d i r e c t l y by m e t a p l a s i a o f p r e  e x i s t i n g p r i m i t i v e t o t i p o t e n t i a l mesenchymal c e l l s i n the area (21, 35, 76, 148). A more w i d e l y accepted concept i s t h a t d i s  c o n t i n u i t i e s i n the i n t e r n a l e l a s t i c lamina a l l o w the a c t i v e m i g r a t i o n o f smooth muscle c e l l s from the media by growth and amoeboid a c t i o n . With l i g h t and e l e c t r o n microscopy smooth muscle c e l l s o f the media have demonstrated o r i e n t a t i o n w i t h p r o c e s s e s extending through gaps i n the i n t e r n a l e l a s t i c lamina i n t o the i n t i m a (8, 34, 53, 54, 112, 131). With the e l e c t r o n microscope mast c e l l s , lymphocytes, monocytes and h i s t i o c y t e s have been seen, i n d i c a t i n g p o s s i b l e p e n e t r a t i o n from the lumen, but these are not c l a i m e d t o g i v e r i s e t o smooth muscle c e l l s or e x t r a c e l l u l a r elements (53, 56, 112). We s t i l l do not know why the smooth muscle c e l l , r a t h e r than the f i b r o b l a s t , appears t o form the i n t i m a , and what i n f l u e n c e s the smooth muscle c e l l t o produce e l a s t i c f i b r e s , c o l l a g e n and a c i d mucopolysaccharides. I t does f u l l f i l l a p a t h o p h y s i o l o g i c a l requirement by r e n d e r i n g t h e , a r e a " e l a s t i c " by v i r t u e o f i t s con t r a c t i l i t y . With a l l the p r e c e d i n g evidence, McMillan (96) s t a t e d t h a t he i s s t i l l not convinced t h a t i t i s p o s s i b l e t o t e l l i f these c e l l s are l e s s d i f f e r e n t i a t e d mesenchymal c e l l s t h a t are assuming a d i f f e r e n t i a t i o n resembling t h a t o f smooth muscle, or whether they are a p a t h o l o g i c a l a l t e r a t i o n i n the normal c y t o - d i f f e r e n t i a t i o n o f smooth muscle c e l l s . I n t e r n a l E l a s t i c Lamina change As p r e v i o u s l y mentioned, changes from the normal i n t a c t - 11 - e l a s t i c lamina which i s a smooth, l o n g i t u d i n a l l y corrugated, con tinuous, homogeneous subendothelial tube with fenestrations, have been seen as early as 36 weeks of gestation. These changes consist of l o c a l i z e d stretching, fraying, and s p l i t t i n g , with rupture or degeneration, forming d i s c o n t i n u i t i e s i n the lamina. The e l a s t i c lamina i s often seen to be s p l i t , an appearance which either represents formation of new e l a s t i c f i b r e s by the smooth muscle c e l l s or a true s p l i t t i n g of the o r i g i n a l e l a s t i c lamina. Eventually t h i s destruction or reorientation of e l a s t i c t i s s u e r e s u l t s i n a complete disappearance of the o r i g i n a l normal i n t e r n a l e l a s t i c lamina (17, 29, 34, 88, 99, 105, 108, 109, 117, 142, 150). Simultaneous with the above process i s the production of a network of new d e l i c a t e wavy e l a s t i c f i b r i l s arranged i n layers between the c i r c u l a r l y arranged smooth muscle bundles (29, 53, 99, 108). Depending on the association of these new f i b r e s with large amounts of collagen or smooth muscle tissu e they formerly were re f e r r e d to as the e l a s t i c - h y p e r p l a s t i c or musculo-elastic layers (40, 41, 108). This new e l a s t i c tissue has been shown to be d i f f e r e n t from the i n t e r n a l e l a s t i c lamina and therefore not simply degenerating or c a l c i f y i n g o ld e l a s t i c elements of the lamina, by the demonstration of altered staining properties of the new f i b r e s (21). I f t h i s were a ph y s i o l o g i c a l e f f o r t to re produce a new i n t e r n a l e l a s t i c lamina, i d e n t i c a l staining reactions might be expected. A gradual t r a n s i t i o n from the e a r l i e s t new f i b r e s to the l a t e r lesions has been demonstrated (59, 88). Under the l i g h t microscope the e a r l i e s t changes were - 12 - accompanied by a swelling of the hyalin core of the internal elastic lamina with an appearance of bead-like material coating the lamina (59, 105). Under the electron microscope these beads have been identified as new fragments of elastin (53). The f i r s t lesions consisting of swelling and decreased density of the i n  ternal elastic lamina have been interpreted as lipoidal degener ation or lip i d s entering into elastic protein to form a solid solution of lipoprotein in and around elastic tissue. (3,6, 120, 148, 105). There i s some evidence to support the idea that l i p i d imbition represents the primary insult to the arterial wall (44), but i t may also be that l i p i d i s deposited i n the wall because i t s transfer i s blocked by the abnormal intima. Appearing later (nine years of age) i s a progressive deposition of calcium either on the surface or within the sub stance of the elastic elements which has been considered as a manifestation of aging and possibly the source of calcium in the later degenerative lesions (4, 21, 84, 104, 114). The function of the internal elastic lamina i s to passive ly prevent over-stretching of the arterial wall by maintaining tension against the distending force of blood pressure. The medial smooth^muscle, by active contraction, also contributes to the main tenance of tension but requires a continuous expenditure of energy and so i s less e f f i c i e n t . The peculiar elastic behaviour of a blood vessel has been shown to result mainly from the combin ation of elastin and collagen fibres in the wall. ' Slight stretch ing of the wall w i l l put stress on the elastin fibres but the much less extensible collagen fibres do not reach their unstretched - 13 - length u n t i l the vessel i s considerably distended. Therefore the e l a s t i c tissue i s the main control against d i l a t i o n . According to Hooke's Law> as the wall i s stretched i t r e s i s t s , not proport i o n a l l y to each stretch, but more and more strongly at each additional stretch (31, 88). There have been several suggestions as to the cause of degeneration of the i n t e r n a l e l a s t i c lamina including enzymatic reactions and other humoral injurious agents (21), and actual mechanical s p l i t t i n g by the migrating smooth muscle c e l l s (132). The most widely accepted theory i s that of mechanical injury due to stretching by a r i s i n g i n t r a a r t e r i a l pressure, or the prolong ed maintenance of normal pressures which are greater than the t e n s i l e strength of the e l a s t i c tissue (110). whatever the cause of the changes i n the i n t e r n a l e l a s t i c lamina, there i s a r e s u l t  ant loss i n e l a s t i c i t y and decrease i n the t e n s i l e strength of the wall, and t h i s i s followed by an attempt to reconstruct new e l a s t i c tissue to compensate (21, 76, 88, 105, 110). I t has been suggested and q u a l i t a t i v e l y shown that the amount of intimal growth i s associated with the number of breaks or changes i n the e l a s t i c lamina, i n d i c a t i n g that both are part of a reparative process (7, 63, 91, 129, 131, 147). This i s also supported by the fa c t that electron microscopy has shown the-smooth muscle c e l l s to beproducing the new e l a s t i n . Mucopolysaccharide Changes The accumulation of small amounts of acid-mucopolysacchar- ide i s recognized as one of the e a r l i e s t changes i n the subendo- t h e l i a l area (21, 59, 108, 110, 125, 142, 150, 161). - 14 - I n the normal i n t i m a , the i n t e r n a l e l a s t i c lamina i s encased i n a p o o l o f mucopolysaccharide (124, 163). A l t e r a t i o n s i n the a c i d mucopolysaccharide are thought t o c o n s t i t u t e a major f e a t  ure i n the pathogenesis o f a r t e r i o s c l e r o s i s as they are c o n s t a n t and prominent f e a t u r e s (16, 106, 128, 150). I t has been shown t h a t a c i d mucopolysaccharides are c o n s t a n t l y a s s o c i a t e d w i t h degenerating areas o f e l a s t i c t i s s u e as seen by i n c r e a s e i n c o n c e n t r a t i o n i n areas o f f r a y i n g and s p l i t t i n g o f the i n t e r n a l e l a s t i c lamina. They are a l s o seen surrounding a l l new e l a s t i c t i s s u e f o r m a t i o n (16, 29, 105, 112, 128, 150, 163). I t was thought t h a t t h i s ground substance was the r e s u l t o f the degen e r a t i n g e l a s t i n (21, 111, 150), an i m b i t i o n o f an imperfect, p o s s i b l y depolymerized ground substance, or p a r t i a l l y d e r i v e d from mast c e l l s (128). However, i t i s p r o b a b l y an e x t r a c e l l u l a r s e c r e t o r y p r o d u c t o f the smooth muscle c e l l s (16, 106, 128, 155) and i t i s formed as a p r e c u r s o r f o r i n c o r p o r a t i o n i n t o c o l l a g e n and e l a s t i c f i b r e s (26, 105, 150). T h i s i s s i m i l a r t o any r e g e n e r a t i v e p r o c e s s i n the body a f t e r some i n j u r y (34, 59, 140). The a c i d mucopolysaccharides have been shown to i n c r e a s e q u a n t i  t a t i v e l y w i t h age, up t o about 50 y e a r s , i n a s s o c i a t i o n w i t h the growth o f the i n t i m a (9, 17, 29, 84, 110, 163). 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 study has been found t o v e r i f y these q u a n t i t a t i v e statements. Along w i t h the q u a n t i t a t i v e age changes t h e r e i s a q u a l i t a t i v e change i n the ground substance. The i n f a n t i n t i m a c o n t a i n s h y a l u r o n i c a c i d as the major component o f the ground substance. By h i s t o c h e m i c a l s t u d i e s the f o l l o w i n g changes have been found t o occur w i t h i n c r e a s i n g age: (16,17,32, 155, 163). - 15 - 1. There i s a r e l a t i v e and absolute increase i n sulfon ated acid mucopolysaccharides and acid mucopolysacch arides bound with proteins, mainly chondroitin sulfate A and C (especially after age 20 years) along with chondroitin s u l f a t e B, h e p a r i t i n sulfate, alpha-heparin, and kerato s u l f a t e . 2. There i s an increase i n neutral mucopolysaccharides and s i a l i c acids. These same variations were found i n the e x t r a c e l l u l a r as well as i n t r a c e l l u l a r areas i n d i c a t i n g the area of production. In addition to the r o l e of mucopolysaccharides i n the form ation of f i b r e s , the change i n the type of ground substances may contribute to an a l t e r a t i o n of the permeability of the subendo- t h e l i a l tissues which may f a c i l i t a t e the trapping'of subtances i n the intima, or influence the l o c a l metabolism of l i p i d s (26, 32, 58, 128, 150, 155). The changes i n mucopolysaccharide metabolism may r e f l e c t a change to an abnormal a c t i v i t y of the intimal f i b r o b l a s t i c c e l l s to produce excess sulfonated acid mucopolysaccharides. In c e r t a i n i n h e r i t e d disorders of connective tiss u e (Hurler's Syndrome or Gargoylism) there i s a severe disturbance i n mucopolysaccharide- metabolism. This i s demonstrated by an excess secretion of chondroitin s u l f a t e B and h e p a r i t i n s u l f a t e . The r e s u l t s of t h i s defect are r e f l e c t e d i n a l l areas of the body including the a r t e r i a l intima which shows tremendous hyperplasia with mucopoly saccharide deposition, e s p e c i a l l y i n the coronary a r t e r i e s (94, 100). - le - As has already been described, there i s an increasing amount of collagen deposition i n the intima with age. This i s a r e f l e c t i o n of a reinforcement mechanism to strengthen the a r t e r i a l wall at the s i t e s of i n t e r n a l e l a s t i c lamina destruction. The collagen consists of f i n e and coarse collagen f i b r e s . The young intima consists c h i e f l y of fine collagen which i s e a s i l y soluble by collagenase. The r a t i o of coarse to f i n e f i b r e s increases with age and severity of e l a s t i c change (163). Collagen f i b r e s have been seen binding together ruptured ends of the i n t e r n a l e l a s t i c lamina (163)-.and e l a s t i c f i b r e s are surrounded by a compact net work of r e t i c u l a r f i b r e s . The collagen f i b r e s are presumably synthesized by the smooth muscle c e l l s perhaps u t i l i z i n g the carbo hydrate macromolecules as a template or pattern on which the protein molecules are oriented to form the collagen. The following protein changes occur with age (155): 1. There i s an increase i n tyrosine, cysteine, r e t i c u l i n , f u c hsinophilic procollagen and e l a s t i n . 2. There i s an increase of b i - r e f r a c t i v e scleroproteins. In the f i r s t two decades the collagen present i n the intima exists mainly as a weakly polymerized solution of p a r t i c u l a t e macromole cules, because the predominant substance present i s hyaluronic acid, which does not form permanent bonds with proteins, and whose mole cule, because of i t s large size, prevents f i b r i l l a r y accumulation and p r e c i p i t a t i o n of polypeptide chains i n collagen solutions. After the second decade, the production of sulfonated acid mucopolysacc harides, which are small molecules, i s unable to prevent the accumu l a t i o n and p r e c i p i t a t i o n of polypeptide chains into collagen - 17 - solutions. Stable bonds between the proteins and acid mucopoly saccharides form f i b r i l s and f i b r e s . Fine e a s i l y d i g e s t i b l e collagen i s c h i e f l y associated with chondroitin sulfates A and C, whereas older coarse f i b r e s are most frequently connected with chondroitin s u l f a t e B. The r a t i o of chondroitin s u l f a t e B to chondroitin sulfate A and C increases with age (17, 155, 163). The medial changes consist of a constant increase i n thick ness with general body and heart growth, with the greatest increase i n number of e l a s t i c f i b r e s and smooth muscle c e l l s occurring i n the f i r s t two decades (61). Starting i n the second decade, the coronary artery media has decreased e l a s t i c i t y with clear cut c a l c i  f i c changes of the e l a s t i c tissue, along with fraying, fragmentation and regeneration of the f i b r e s , s imilar to the process i n the intima (84). These new and degenerating e l a s t i c components seem to have an a f f i n i t y for calcium. There i s s t i l l a constant t o t a l e l a s t i n content after the second decade i n d i c a t i n g that the loss of e l a s t i  c i t y i s probably due to the c l a c i f i c a t i o n rather than the loss of e l a s t i c t i s s u e . I t i s postulated that these changes may e s t a b l i s h a substrate for l a t e r l i p i d changes, but also they are claimed to be an independent process unrelated to atherosclerosis and probably a coincidental association with i t , i n the coronary artery (29, 85, 104). I f one accepts the theory that mechanical injury stimulates i n t i m a l hyperplasia, then a loss of e l a s t i c i t y of the media would make the weakened a r t e r i a l wall more susceptible to the forces of intravascular pressure. However, t h i s loss of e l a s t i c i t y due to c a l c i f i c a t i o n has not been demons t r at ed|' i n infants when the intima i s already thickening. C a l c i f i c a t i o n may contribute to l a t e r - 18 - p r o l i f e r a t i o n (17, 24). Changes i n the i n t e r n a l e l a s t i c lamina are accompanied by important e f f e c t s on the smooth muscle of the media. Large numbers of the c e l l s near the i n t e r n a l e l a s t i c lamina turn inwards forming an inner r a d i a l coat, and are then seen to penetrate i n t o the subendothelium where they continue to p r o l i f e r a t e (117,133). L o c a l i z a t i o n of lesions I t i s generally agreed that the intima of the coronary artery has a greater r e l a t i v e growth than that of any other vessel i n the body (61, 131, 137, 138). Before there i s generalized intimal thickening, only segments of the coronary artery are involv ed (159). I t may well be that l o c a l anatomical factors determine the s i t e s of lesions, as the affected areas i n infants are usually the same s i t e s as i n adult a r t e r i o s c l e r o s i s (55, 88, 103). There i s , however, not a complete uniformity i n s i m i l a r situations i n the i n d i v i d u a l coronary or at the same s i t e s i n d i f f e r e n t i n d i v i d  uals. Hyperplasia of the intima i s most pronounced i n the proximal portions of the l e f t and r i g h t coronary vessels (53, 61, 101,158). In infancy as well as l a t e r i n l i f e , the e p i c a r d i a l portions of the coronary vessels have been found to have a much thicker intima than the mural portions, or the parts invested by myocardium, suggesting some mechanical influence (37, 38, 50, 57). This helps to support mechanical theories of etiology e s p e c i a l l y those involving i n t r a  vascular pressure and shearing stress. I t has also been noted that there i s an increase i n intimal thickness at the s i t e of branches or B i f u r c a t i o n of the coronary vessels suggesting a hemodynamic e f f e c t (48, 61, 127, 152). This i s linked with the f o e t a l intimal - 19 - muscular cushions which have been observed at mouths of branches of the coronary a r t e r i e s as well as other muscular a r t e r i e s (36, 132, 157). These cushions of longitudinal muscle and e l a s t i c tissue:.have been interpreted by some as a means to regulate the blood flow to the branch (38, 139, 157) but generally are consid ered to be a reaction to hemodynamic stress; i . e . , a buffer zone or a remodelling for wall reinforcement, which i s i n continuity with, or w i l l develop into the picture of intimal hyperplasia which has been described (29, 34, 131, 132, 133). In the r i g h t coronary artery of the dog the d i s t r i b u t i o n of maximal hyperplasia was similar to that of the human. The changes were i n the proximal two centimeters on either side of the sino a t r i a l and conus artery o r i g i n s and continuing i n t o the two branch ar t e r i e s , and at the v e n t r i c u l a r branch at the margo acutus (25, 61). I t i s claimed by many investigators that intimal thickening occurs more frequently and e a r l i e r i n the l e f t coronary artery, p a r t i c u l a r l y i n the anterior descending branch, than i n the r i g h t coronary (40, 47, 61, 101). This i s thought to be p a r t l y due to the fact that the l e f t coronary artery i s subject to more tensions than the r i g h t during the cardiac cycle (85, 110). Others claim that any difference i n intimal hyperplasia i n the three major vessels, ( l e f t anterior descending, l e f t circumflex, and r i g h t coronary) are 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 (13, 72, 91, 111). However, whether there i s a quantitative difference between l e f t and r i g h t coronaries or not, there i s general agreement that the pattern of development of intimal hyperplasia i s similar i n both, - 20 - l e a d i n g t o the c o n c l u s i o n t h a t the same pro c e s s operates i n the two a r t e r i e s (64, 98, 158). D e f i n i t i o n o f terms A r t e r i o s c l e r o s i s means, l i t e r a l l y , "hardening o f the a r t e r i e s " and was used f i r s t by L o b s t i e n i n 1829 (14, 121) t o d e s c r i b e the t h i c k e n i n g and hardening o f the w a l l s o f the a r t e r i e s . I t i s a term used t o d e s c r i b e a complex mixture o f de g e n e r a t i v e and r e p a r a  t i v e p r o c e s s e s which l e a d t o i n c r e a s e d r i g i d i t y , d i m i n i s h e d e l a s t i  c i t y , and o f t e n decreased c a l i b r e o f a r t e r i e s , commonly accentuat ed a t f o c a l p o i n t s , b ut wit h a tendency t o spread and become c o n f l u e n t (21, 22, 23, 65). I t i s the r e s u l t o f many types o f e t i o l o g y and pathogenesis. I t -".includes d i s o r d e r s o f l a r g e and s m a l l a r t e r i e s a f f e c t i n g the i n t i m a , such as a t h e r o s c l e r o s i s , e l a s t o s i s , r e g e n e r a t i v e i n t i m a l t h i c k e n i n g , and the acute form o f Raynaud's d i s e a s e , and d i s o r d e r s a f f e c t i n g the media, such as medial hypertrophy or atrophy, Monkeberg's d i s e a s e , c y s t i c and f a t t y d e g e n e r a t i o n . T h e r e f o r e a r t e r i o s c l e r o s i s encompasses the r e a c t i o n o f the t o t a l a r t e r i a l w a l l as r e p r e s e n t e d by i t s components. A t h e r o s c l e r o s i s i s a type of a r t e r i o s c l e r o s i s and t h e r e f o r e a more s p e c i f i c term (96). I t was used f i r s t by Marchand i n 1904 (121) t o d e s c r i b e the p r o c e s s o f the primary f a t t y and atheroma tous degeneration o f the a r t e r i a l i n t i m a (14). A W.H.O. t e c h  n i c a l r e p o r t (210) d e s c r i b e d a t h e r o s c l e r o s i s as "a v a r i a b l e combin a t i o n o f changes o f the i n t i m a o f a r t e r i e s c o n s i s t i n g of the f o c a l accumulation o f l i p i d s , complex carbohydrates, b l o o d and b l o o d products, f i b r o u s t i s s u e and c a l c i u m d e p o s i t s , and a s s o c i a t e d w i t h medial change." (19). I t i s a n u t r i t i o n a l - m e t a b o l i c d i s e a s e - 21 - o f m u l t i f a c t o r i a l c a u s a t i o n (46, 78, 145). I n t i m a l h y p e r p l a s i a i s t h e r e f o r e an e a r l y i n d i c a t i o n o f a r t e r i o s c l e r o s i s as any forms o f t h i s d i s e a s e which i n v o l v e i n t i m a l l e s i o n s must occur i n t h i s t h i c k e n e d i n t i m a . To d e f i n e a r t e r i o s c l e r o s i s one must i n c l u d e primary c o n t r i b u t o r s t o i t s morphology and pathogenesis such as the i n t i m a l h y p e r p l a s i a , changes i n the i n t e r n a l e l a s t i c lamina and medial changes (109). J o r e s went so f a r as t o c l a i m t h a t any s p l i t t i n g o f the i n t e r n a l e l a s t i c lamina i s a m a n i f e s t a t i o n o f a r t e r i o s c l e r o s i s (95). Even authors who c o n s i d e r the i n t i m a l growth a "normal" p h y s i o  l o g i c a l response r e c o g n i z e t h a t t h e r e i s a t r a n s i t i o n t o a p a t h  o l o g i c a l p r o c e s s c o n s i s t e n t with a r t e r i o s c l e r o s i s (101, 110, 139). The i n t i m a l l a y e r o f the a r t e r i a l w a l l has been c o n s i d e r e d t o be a pre-atheromatous p r o l i f e r a t i o n (35, 46, 62, 108, 159) b u t s i n c e a t h e r o s c l e r o s i s has a c o m p l i c a t e d pathogenesis the a s s o c i a t i o n i s s t i l l not completely c l e a r (29, 56, 66, 103). I n t i m a l f i b r o u s t h i c k e n i n g o f a r t e r i e s i s a p r o g r e s s i v e p rocess, p r o b a b l y a g e - r e l a t e d (1, 4 ) . I t i s necessary t o e s t a b l i s h a d i s  t i n c t cause and e f f e c t r e l a t i o n s h i p between these changes and the a t h e r o s c l e r o t i c p r o c e s s , as f a t t y s t r e a k s have been seen without i n t i m a l t h i c k e n i n g . I t has been demonstrated t h a t t h e r e i s a d i r e c t r e l a t i o n s h i p between the frequency and s e v e r i t y o f atheroma and the e x t e n t o f the s u b e n d o t h e l i a l growth (40, 41, 49, 61, 112). G e i r i n g e r (57) c l a i m s t h a t t h e r e i s a c r i t i c a l depth o f the coron ary i n t i m a o f 0.35 mm. a f t e r which the chances o f atheroma develop ment are g r e a t l y i n c r e a s e d . The e a r l i e s t r e c o g n i z a b l e l e s i o n o f a t h e r o s c l e r o s i s i s c l a i m e d by many t o be the e a r l y l i p i d seen i n the - 22 - hypertrophied intima (4, 35, 55, 109). 'The decreased p l i a b i l i t y and e l a s t i c i t y of the thickened intima may promote a change i n metabolism of intimal c e l l s which encourages l i p i d deposition, (41). There i s a continuous sequential change from childhood to adult l i f e which suggests that the early micro-alterations i n the subendothelium precede, and probably lay the ground work for the l i p i d deposition, h y a l i n i z a t i o n , and c a l c i f i c a t i o n of atheromatous plaques (63). Even authors who claim that intimal hyperplasia i s not e s s e n t i a l for atherosclerosis admit that i t s presence seems to favour l i p i d deposition (148). Accepting the concept that atherosclerosis has i t s beginning i n infancy, a study to elucidate i t s etiology and pathogenesis must focus on the incubation period of the disease rather than on i t s advanced manifestations and complications. The process must be followed from i t s inception i n the p e r i n a t a l period through childhood and adolescence into adult l i f e i n order to reconstruct the histogenesis of late, c l i n i c a l l y important lesions. The f o c a l point for a l l the changes i n atherosclerosis i s the a r t e r i a l wall- I t therefore must be studied from a l l angles. Past correlations of intimal hyperplasia with various factors. A. Age and media: The q u a l i t a t i v e r e l a t i o n s h i p of intimal hyperplasia with age has been discussed. There have been numerous descriptions of the progressive changes i n the intima with increasing age but few quantitative studies. The f i r s t evidence of such a study was by Mann i n 1912 (97) who measured the intima of the aorta i n microns at d i f f e r e n t ages and found a l i n e a r r e l a t i o n s h i p with age: - 23 - Age Intima Media Newborn 6 650 16 years 54 856 35 years 124 996 Only three specimens were used to e s t a b l i s h t h i s r e l a t i o n s h i p i n the newborn to the 4th decade period! Since then, f i v e authors have produced some quantitative evidence showing a progressive intimal increase with age. Moon et. a l . inl952 (107) showed a l i n e a r r e l a t i o n s h i p of intima versus age i n the range 0-30 years but f a i l e d to state the number of specimens used or how they were evaluated. Groom et. a l . i n 1964 (63) showed a similar r e l a t i o n  ship i n 177 specimens but used average percentage encroachment on the lumen as a c r i t e r i o n . Neufeld et. a l . i n 1962 (116) showed a progressive increase with age of the r a t i o of the intima to the t o t a l vessel thickness using 100 hearts but f a i l e d to produce evidence to show 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 r e l a t i o n s h i p ; as h i s graphs do not show one. Levene i n 1956 (89) used 98 hearts to show an age-intima r e l a t i o n s h i p but h i s graph-S also raises doubts as to the s i g n i f i c a n c e of the intimal growth i n the 0-20 age groups. Lober i n 1953 (91), using 173 specimens i n the 0-30 year range, measured the thickness of the intima as a percentage thickness.; of the a r t e r i a l wall and r e l a t e d the averages to age producing a very convincing graph, but s t i l l f a i l e d to v e r i f y i t s t a t i s t i  c a l l y . Although some of the previous workers have mentioned using the proximal parts of the coronary a r t e r i e s with the larger amounts of hyperplasia, none other than Moon et. a l . (107) mentioned or used multiple sections along the vessel. - 24 - Most have r e l a t e d the i n t i m a l t h i c k n e s s t o the media (137) or t o the t o t a l a r t e r i a l w a l l (37, 91, 116) b e f o r e r e l a t i n g i t t o age, r a t h e r than working out a d i r e c t r e l a t i o n s h i p . Since h i s t o l o g i c a l f e a t u r e s are non-uniform i n t h e i r d i s  t r i b u t i o n throughout the coronary a r t e r i a l t r e e the element o f chance can be minimized on l y by numerous measurements e i t h e r by s e r i a l c r o s s s e c t i o n s or by m u l t i p l e l o n g i t u d i n a l s e c t i o n s . A l s o , q u a n t i t a t i v e judgements o f s m a l l g r a d a t i o n s o f i n t i m a l h y p e r p l a s i a are d i f f i c u l t t e c h n i c a l l y . Any e r r o r s i n measurements can be m i n i  mized by the examination o f a l l specimens by one o b s e r v e r . I g n o r i n g c r i t i c i s m s , these e a r l i e r s t u d i e s have shown.a p r o g r e s s i v e i n c r e a s e o f the i n t i m a from b i r t h t o the 4th decade and beyond. There i s c o n t r o v e r s y as t o the p e r i o d o f maximum r a t e o f i n t i m a l growth. Lober (91) claims- the s h a rpest r i s e i s i n the 20-30 year group, but Groom (100) and Moon (105) s t a t e t h a t the most r a p i d r a t e o f i n t i m a l growth occurs f o r s e v e r a l months 4^, f o l l o w i n g b i r t h and then slows. There i s evidence t o show t h a t the t h i c k n e s s o f the media p r o g r e s s i v e l y i n c r e a s e s with age but the i n t i m a l t h i c k n e s s i n c r e a s  es r e l a t i v e l y more r a p i d l y than the media and t h e r e i s t h e r e f o r e a r i s e o f r e l a t i v e i n t i m a l t h i c k n e s s w i t h age (89, 91, 116). There i s a l s o evidence t h a t the mean e x t e r n a l diameter o f the coronary a r t e r y i n c r e a s e s w i t h age (116). B. I n t e r n a l E l a s t i c Lamina: The p r o g r e s s i v e age changes o f f r a y i n g , fragmentation and p r o d u c t i o n o f i n t i m a l e l a s t i c t i s s u e have been d e s c r i b e d . Many authors have r e m a r k e d on the c l o s e a s s o c i a t i o n o f the amount o f e l a s t i c change with the growth of the intima and suggested a causal r e l a t i o n s h i p between the two events (131). However, few have attempted to quantitate e l a s t i c change. Moon et. a l , 1952, (107) produced a graph showing the e l a s t i c degeneration versus age but f a i l e d to say how he arrived at the r e s u l t s . Groom et a l , 1964, (63) graphed the q u a l i t a t i v e presence of fraying or fragment ation of the i n t e r n a l e l a s t i c membrane which too, showed a progress ive increase with age. He also f a i l e d to give d e t a i l s as to h i s methods. Lober, 1953, (91) graded the amount of e l a s t i c lamina change from 0 - 1 2 years, and p l o t t e d t h i s against age producing a s t r a i g h t l i n e increase i n destruction with age. None of these experiments have been v e r i f i e d s t a t i s t i c a l l y . From the preceding r e s u l t s we conclude that there have been i n d i r e c t inferences concerning the r e l a t i o n s h i p of i n t e r n a l e l a s t i c lamina change and intimal thickness, but no d i r e c t i n v e s t i g a t i o n a l work has been found on t h i s subject. C. Sex: Although some studies have f a i l e d to substantiate a d i f f e r  ence between male and female i n the thickness of the intima i n the inf a n t coronary artery (142), most investigators have shown that males have a thicker intima than females from b i r t h onwards (38, 48, 61, 90, 133) suggesting a possible hormonal factor. Dock, 1946, (37) examined the coronary a r t e r i e s of 12 neonatal infants and showed 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 difference i n the amount of intimal hyperplasia between males and females. Fangman and Hellwig, 1947, (51) also used 12 infants to draw the same conclusions. Their studies have been c r i t i s i z e d for the small number of specimens, - 26 - (112, 139). Minkowski, 1947, (103) demonstrated a sex difference i n infants older than 24 hours which i s supported with s t a t i s t i  c a l evidence by Lober, 1953 (91) who found a s i g n i f i c a n t d i f f e r  ence over the age of one month, using 173 specimens i n the age group 0 - 3 0 . After the age of 10, the progressive rate of intimal growth was shown to be the same i n both sexes even beyond the menopause. This suggests that the hormonal ef f e c t s may not be fundamental. Using 400 specimens from age 20 - 80, Avtandilov, 1963, (13) showed that the sex difference persisted u n t i l age 60, after which there was no difference. The only study r e l a t i n g i n t e r n a l e l a s t i c lamina.degenera t i o n to age was done by Lober, 1953, (91) who demonstrated an increase i n e l a s t i c lamina changes i n males compared to females at a l l ages but states that the only group s t a t i s t i c a l l y s i g n i f i c a n t i s the 40 - 49 year group. In the l i t e r a t u r e we reviewed, we found no studies r e l a t i n g intimal hyperplasia or e l a s t i c change to body weight, heart weight, or blood pressure even though hypertension appears to increase the incidence of c l i n i c a l coronary disease. I t i s generally acknow ledged that diabetes tends to cause c l i n i c a l coronary disease to develop at an e a r l i e r age than i n a non-diabetic person (91). Also, there are inferences to suggest that there i s an increase i n intimal thickness i n in d i v i d u a l s with many forms of chronic disease, but there are no studies to substantiate these theories. There are reported studies showing a difference i n intimal hyperplasia i n d i f f e r e n t races (49, 133). But i n each case i t i s a comparison of an American white population with a race i n some other part of the world or of a completely d i f f e r e n t socio economic background. Supporting t h i s Groom et. a l . (63) used ge n e t i c a l l y s i m i l a r populations from d i f f e r e n t countries and showed a s i g n i f i c a n t difference i n the amount of intimal thicken ing, i n t e r n a l e l a s t i c lamina changes, and gross atheromatous lesio n s . - 28 - THEORIES OF ETIOLOGY OF INTIMAL HYPERPLASIA Although much has been written on the subject of the e t i o l  ogy of intimal hyperplasia, i t i s s t i l l poorly understood and there i s very l i t t l e d e f i n i t e knowledge about the etiology. I t i s es s e n t i a l to determine why and how ce r t a i n changes take place and to understand the mode of the development. This might aid us i n d i r e c t i n g an i n t e l l i g e n t approach to prevention and treatment of a r t e r i a l disease. Since the changes of intimal hyperplasia are part of a process which predisposes to, or causes, eventual dysfunction they are, by d e f i n i t i o n , considered to be pathologic. These changes progress with age but are more than a simple process of aging, as d i f f e r e n t s i t e s i n d i f f e r e n t a r t e r i e s manifest changes i n d i f f e r e n t degrees at d i f f e r e n t times. The actual causes of intimal p r o l i f e r a t i o n are unknown but are considered to be a combin ation of many factors, both l o c a l , (e.g. altered metabolism and permeability i n the vessel wall) and systemic influences, (e.g. endogenous or exogenous factors i n the blood, hemodynamic forces, genetic and environmental influences, and intercurrent disease). (46, 50, 61, 62, 66, 73, 106, 111, 142, 144) I t i s generally agreed that the early intimal hyperplasia of the coronary a r t e r i e s represents a phenomenon of adaptation to high demands made on these vessels i n the f i r s t months of l i f e , which continues i n t o l a t e r l i f e . An early explanation of the process of intimal hyperplasia was given by Virchow (1856) (56) who believed i t to be a primary inflammatory overgrowth of the intimal connective tissue r e s u l t i n g from mechanical i r r i t a t i o n of the a r t e r i a l wall by the pressure of the blood at c r i t i c a l points. This overgrowth of the intima would i n t e r f e r e with the n u t r i t i o n of the c e l l s . Rokitansky (1852) (136) held an opposing view that the s t r a t i f i e d hypertrophy of the intima was the r e s u l t of an excessive deposition of a fibrinous substance derived from the blood on the l i n i n g . Thoma (1911, (153) believed that the intimal hyperplasia was due to i r r i t a t i o n of the wall, not only by mechanical factors, but also by a toxic substance i n the blood, probably a metabolic product.(82) Since the 19th century, numerous theories have been proposed for the etiology of intimal hyperplasia, but b a s i c a l l y a l l of them are variants of the three above mentioned theories. The most widely accepted concept i s that intimal p r o l i f e r a t i o n i s s i m i l a r or i d e n t i c a l to a connective t i s s u e reparative process following i n j u r y (23, 59, 62, 106). Whether a continuous stress i s present, or multiple recurring small episodes, the a r t e r i a l wall attempts to reform a s t r u c t u r a l l y sound wall (147), i . e . the various components of the a r t e r i a l wall attempt to adjust to changes i n l o c a l environment (21). Any type of i n s u l t to the a r t e r i a l wall i n t e r f e r e s with oxygenation and n u t r i t i o n of the vascular wall, leading to degenerative and p r o l i f e r a t i v e changes. This i s probab l y the fundamental causal mechanism regardless of e t i o l o g i c a l agent (73). The e t i o l o g i c a l agents can be summarized i n four groups: 1. physiologic and pathologic mechanical trauma. 2. metabolic e f f e c t s including physiochemical disturbances of the blood, of endocrine, vitamin, or n u t r i t i v e o r i g i n . - 30 - 3. inflammatory agents 4. physiologic aging processes Regardless of the s p e c i f i c physiologic a l t e r a t i o n i n the wall, the h i s t o l o g i c reaction to in j u r y i s always the same, namely a p r o l i f e r a t i o n of the int i m a l connective tissue (50, 105). Assuming an injury i s the i n i t i a t i n g event i n the process of intimal hyperplasia (34, 125) which i s manifested by the early changes i n the i n t e r n a l e l a s t i c lamina and i n t e r c e l l u l a r substance (102, 114), what are the forces that produce the injury? Since intimal hyperplasia i s not diffuse, but i s l o c a l i z e d i n c e r t a i n » a r t e r i e s , and even c e r t a i n s i t e s within these a r t e r i e s , these forces must be l o c a l i z e d , at l e a s t p a r t i a l l y (46, 50, 152). In the l i t e r a t u r e innumerable factors have been implicated as injurious agents to the a r t e r i a l wall, the general classes of which are sum marized above. Only a few of the most important ones w i l l be d i s  cussed below. PHYSIOLOGIC AND MECHANICAL TRAUMA. Although numerous factors are involved, many authors agree with Virchow 1s view that mechanical i n j u r y i s a major i n i t i a t i n g cause. The mechanical theory of the genesis of intimal hyperplasia i s that the changes are the end r e s u l t of general and l o c a l hemo dynamic factors acting over a long period of time, and a a r e s u l t of t h i s wear and tear by such forces the artery undergoes a repara t i v e process, an an adaptation or compensation, to maintain a r e l a  t i v e constancy of the mechanics of blood flow. That i s , intimal hyperplasia i s a sequel to f l u i d dynamics applied to the vascular - 31 - system which i s modified by other secondary factors such as age, sex, n u t r i t i o n , l i p i d metabolism, hormones, drugs, associated diseases, and other causes (20, 109, 151). But i t i s b a s i c a l l y the mechanical factors which are contributory (4, 112). As has been stated, the i n i t i a l event i s probably the i n t e r n a l e l a s t i c lamina change which can r e s u l t from i n t r a  a r t e r i a l tensions greater than the t e n s i l e strength of the e l a s t i c t i s s u e (107, 135) and lack of support from a possible r e l a t i v e medial weakness (33, 88, 131, 149). The degree of intimal hyperplasia has been postulated to vary with the amount of hydraulic tension, augmented by other hemodynamic factors (22, 143). The other hemodynamic factors which are contributory are intravascular pressure, cardiac thrust, v i b  r a t i o n , volume flow, g r a v i t a t i o n a l forces, v i s c o s i t y and f r i c t i o n , and shearing forces (22). The coronary a r t e r i e s , because of t h e i r p o s i t i o n as branches of the f i r s t part of the aorta, are subject to exceptional hemo dynamic forces. They are subject to unusually high pressures because while they are pumped f u l l of blood under high pressure they are also subject to pressure from outside due to myocardial contraction. This wide range of pressure which occurs i n the coronary a r t e r i e s , because of t h e i r proximity to a high pressure system, (accentuated by the e l a s t i c r e c o i l of the aorta) and t h e i r proximity to the v e n t r i c l e s , must have some bearing on the severity of intimal hyperplasia i n them (4,5, 32, 40, 50, 52, 85). They also have a fi x e d o r i g i n and are fi x e d where they branch or enter the myocardium (20). Between these areas there i s considerable - 32 - movement where there i s l i t t l e outside support. Supporting a mechanical causation i s the fac t that the areas of maximal intimal hyperplasia usually are found at areas of altered hemodynamic forces. These areas are where the art e r i e s taper, curve, b i f u r c a t e , and at the mouths of branches (20, 40, 55, 85, 115, 117, 127, 131, 132, 151, 152). I t i s at these s i t e s that the maximum e f f e c t of pulsation and turbulence from changes i n d i r e c t i o n a l flow are f e l t . From t h i s pulsation turbulence and changing lengths during the cardiac cycle, shear ing stresses r e s u l t at branchings and angulations i n the l i n e s of l e a s t resistance and of possible cleavage(at the i n t e r n a l e l a s t i c lamina-media junction, due to t h e i r d i f f e r e n t stretch capacity). This can cause injury and i n i t i a t e a reparative process (2, 6, 7, 41, 133). Viscus drag of the blood also helps to produce a l o n g i  tudinal movement of the inner part of the wall, therefore c o n t r i  buting to the shearing stress (92). Also at these s i t e s of curves i s the postulated hemo dynamic suction pressure and l i f t i n g action of blood flow on the intima. This i s due to the negative pressure engendered by the conversion of p o t e n t i a l energy to k i n e t i c energy i n a flow ing l i q u i d when i t traverses a c o n s t r i c t i o n i n a tube ( B e r n o u i l l i ' s Theorem). The suction and l i f t i n g action contribute to eddying and turbulence (31, 36, 45, 82, 92, 151). I t has been found that i n the e p i c a r d i a l or proximal portion of the coronary a r t e r i e s there i s much greater intimal hyperplasia. The wall of the e p i c a r d i a l coronary artery may be thicker by 33% than that of the mural part (139). In t h i s area, - 33 - unprotected by the myocardium, the hemodynamic forces from over- distention, changing lengths, and angulations are greatest. This i s the only difference from the mural portion of the same artery (57, 108). Following on t h i s , since males generally have slower pulses and higher stroke volumes than females, and therefore greater stresses to t h i s part of the coronary artery, males should have a thicker intima (37). With an increase i n blood pressure a l l the hemodynamic forces would be increased and therefore increases of intimal thickness would be expected. This has been confirmed (110, 158, 159). Supporting the mechanical injury concept i s experimental evidence i n animals. Following acute mechanical i n j u r y to the a r t e r i a l wall there i s a degeneration followed by a reparative process h i s t o l o g i c a l l y s i m i l a r to intimal hyperplasia i n humans (67, 79, 118, 140, 142, 152). Intimal hyperplasia has a l l the earmarks of a compensat ory process or adaptation to a progressively r i s i n g i n t r a - a r t e r i a l pressure or the prolonged maintenance of normal pressures (30, 110). This implies that intimal hyperplasia i s i n e v i t a b l e and proressive throughout l i f e (109). Blood pressure varies with age and i s c l o s e l y r e l a t e d to height and weight. Although f e t a l i n t r a - a r t e r i a l pressures have not been recorded, there i s s i g n i f  icant increase at the time of b i r t h . S i g n i f i c a n t increases of i n t r a - a r t e r i a l pressure also occur during the adolescent period, and many variatio n s occur at t h i s time before the more stable l e v e l s of adult l i f e . Exercise, excitement, coughing and - 34 - s t r a i n i n g may r a i s e the s y s t o l i c pressure of children as much as 40-50 mm. Hg. above t h e i r usual l e v e l s (164). A l l these changes and fluctuations i n i n t r a - a r t e r i a l pressure may contribute to injury of the vessel w a l l . However, the d e t a i l e d d i s t r i b u t i o n of the lesions cannot be always explained on a hemodynamic basis as the d i s t r i b u t i o n i s not always uniform i n similar s i t e s i n d i f f e r e n t i n d i v i d u a l s , therefore other factors must be operating also (55). Also, since hydraulic stresses are common to a l l , other factors must be responsible, at l e a s t i n some part, to explain tremendous v a r i a t i o n of intimal hyperplasia i n i n d i v i d  uals. METABOLIC INJURY Several investigators have claimed that l i p i d appears by imbibition from the plasma i n the c e l l s and i n t e r c e l l u l a r sub stance of the endothelium and subendothelium before changes occur i n the i n t e r n a l e l a s t i c lamina (8, 113, 154), and that t h i s represents the i n i t i a l process of intimal hyperplasia (51, 86). The intimal f i b r o s i s , i n other words, represents a reactive process to the l i p i d . ( 1 1 0 ) . I t i s true that l i p i d i n the a r t e r i a l wall w i l l stimulate intimal hyperplasia (120), but i t i s usually considered an adjunct to the i n i t i a l process as large studies have revealed that while some early lesions contain l i p i d , i n the majority of cases the l i p i d appears appreciably l a t e r than the fibrous hyperplasia (107, 117). I t i s unusual to f i n d l i p i d i n lesions i n i n d i v i d u a l s under f i v e years of age. :In some diseases r e s u l t i n g from endocrine disturbances, such as diabetes, there i s an increase of intimal hyperplasia i n - 35 - younger i n d i v i d u a l s , implying that the change i n the hormonal content of the body may injure or more probably promote faster growth of the intima (91). Reisman (126) correlated the maximal intimal hyperplasia and i n f i l t r a t i o n i n the male i n the 10 - 20 years period with the maximal androgen production. However, during t h i s adolescent period many other changes take place including increased c a l o r i c , protein,, and vitamin A intake. Balo (14) postulates that the e l a s t i c f i b e r s are reg ulated by pancreatic elastase which i s , i n turn, checked by elastase. i n h i b i t o r s and suggests that an a l t e r a t i o n i n t h i s balance may be contributory. He also suggests that acid-base balance alt e r a t i o n s w i l l i n j u r e e l a s t i c f i b e r s which therefore would implicate many disease processes. Early metabolic changes found i n the a r t e r i a l wall both i n the amount and types of acid mucopolysaccharides, proteins, and l i p i d s are r e f l e c t i o n s of changes i n i t i a t e d by some other process, but they contribute to changing l o c a l metabolism and permeability of the wall (46, 124, 155). Therefore they are important i n the pathogenesis of intimal hyperplasia. There i s much experimental evidence to implicate l i p i d s i n the atherogenic process, but l i t t l e to suggest that they are the i n i t i a l i n s u l t to the a r t e r i a l w a l l . I t has been shown experimentally that l i p i d s are capable of i n j u r i n g the a r t e r i a l wall with a subsequent p r o l i f e r a t i v e reaction mimicking intimal hyperplasia (14, 34, 85, 147, 149). I t i s agreed that l i p i d can contribute i n the stimulus of fibrous hyperplasia, but, for i t to be the i n i t i a l i n s u l t would require that l i p i d be seen early i n - 36 - the process. This has not yet been confirmed. INFLAMMATORY AGENTS There have been claims i n the past that intimal hyper p l a s i a i s an inflammatory process (11, 127). However, other than l o c a l i z e d inflammations such as s y p h i l i t i c a o r t i t i s , inflammatory agents from an i n f e c t i v e organism have no bearing on the a r t e r i o s c l e r o t i c process (23). Experimentally, numerous agents, both organic and inorganic toxins, have been used to injure the a r t e r i a l wall and promote a reaction which w i l l simulate intimal hyperplasia (34). Most of these have been used i n combination with lipemia to promote an atherogenic process. AGING PROCESS Intimal hyperplasia has been considered as a part of a normal growth process or an expression of the constant remodel l i n g of the a r t e r i a l wall as i t increases i n size (53). While the constituents of the wall change i n t h e i r composition with age b i o l o g i c a l l y similar to many other body tissues, aging i s i n s u f f i c i e n t to explain the tremendous v a r i a t i o n i n d i f f e r e n t people with age and i n d i f f e r e n t parts of the a r t e r i a l tree (8, 73, 84, 146). Therefore intimal hyperplasia should not be regard ed as an in e v i t a b l e by-product of senescence alone but as a r e s u l t of the many factors which are operating as an i n d i v i d u a l ages(77). Many writers have postulated a genetic factor influencing the U degree and d i s t r i b u t i o n of intimal hyperplasia,.a theory which i s very d i f f i c u l t to evaluate and prove (38, 50, 52, 108, 123). For example, Nahum (114) suggested that some people are born with e l a s t i c t i s s u e better able to withstand the years of stretching - 37 - and stress. THROMBOGENIC THEORY There are s t i l l investigators who agree b a s i c a l l y with the etiology proposed by Rokitansky (3, 43, 136). That i s , that intimal hyperplasia i s the end product of mural f i b r i n deposits on the intimal surface, r e s u l t i n g i n a pathological process con s i s t i n g of intimal p r o l i f e r a t i o n and thickening. And these lesions are composed of several layers, suggesting recurrent formation of f i b r i n deposits, each followed by f i b r o b l a s t i c p r o l i f e r a t i o n and organization by endothelial c e l l s and c e l l s from the arter i a l wall replacing the thrombus with fibrous tissue (2, 12, 34, 43, 44, 45, 68, 70, 89, 122, 145). This would help to explain the decrease i n lumen si z e with intimal hyperplasia, whereas injury should promote a d i l a t i o n (44, 45, 55). Als o , i n older lesions a continuity between the fibrous and thrombotic lesions has been seen (45). However, these t r a n s i t i o n stages have not been v e r i f i e d i n the very early lesions (161). I t i s d i f f i c u l t to conceive that these early changes r e s u l t from encrustation or imbibition of f i b r i n into the intima. On the other hand i t appears quite reasonable to suspect that l o c a l i z e d areas of tissue injury may be very susceptible to f i b r i n deposition and eventual replacement by fibrous tissue, r e s u l t i n g , after a long period, i n a fibrous plaque. Therefore the thrombogenic process could account for a part of the intimal hyperplasia but c e r t a i n l y not a l l (4, 42, 44, 45). S t i l l , the genesis of primary concentric intimal hyper p l a s i a i s obscure. There i s no fundamental h i s t o l o g i c a l d i f f e r -- 38 - ence between the tissue which can r e s u l t from organization of f i b r i n thrombi and that r e s u l t i n g from the p r o l i f e r a t i o n of mesenchyme. I t i s most l i k e l y that primary intimal hyperplasia i s a r e s u l t of t i s s u e growth i n response to mechanical stress with contribution from the aging process and remodelling due to a r t e r i a l growth. But, recurrent episodes of surface f i b r i n eposition and i t s subsequent incorporation into the intimal fibrous lesions should not be discounted. I t may well be that more than one fundamental process w i l l have to be acknowledged i n t h i s disease (55). - 39 - PROCEDURE :  MATERIALS: The study consisted of an examination of the r i g h t cor onary artery of 101 hearts removed at post-mortem examination during a f i v e month,;period; June to October, 1965. These were c o l l e c t e d from autopsies performed at the Lions Gate Hospital, Saint Paul's Hospital, Royal Columbian Hospital, Vancouver General Hospital, and Vancouver City Morgue. Table I shows the ages of the specimens used. The specimens were taken at random i n the age group 0 - 3 0 years without regard for cause of death. Table II gives a summary of the causes of death. The h o s p i t a l charts and autopsy records were examined to determine age, sex, body height and weight, heart weight, cause of death, and symptoms or signs of any associated diseases. These are summarized with the r e s u l t s of the quantitative examinations (Table IV). The proximal part of the r i g h t coronary artery was remov ed by the pathologist performing the autopsy then fi x e d and pre served i n 10% formal s a l i n e . Depending on the age of the i n d i v  i d u a l and the gross si z e of the vessel the proximal one-half to one centimeter of the artery was used. On d i s s e c t i o n of the speci mens i t was noted that the r i g h t coronary ostium lay near the middle of the r i g h t coronary sinus of Valsalva. In about one- h a l f the hearts there was a second ostium about one mm. away g i v  ing r i s e to the conus artery. (55, 74) This artery was not used i n the study. The main r i g h t coronary artery passed between the - 40 - TABLE I: AGES OF SPECIMENS USED: AGE SEX Male Female Fe t a l 2 1 0 - 1 year;, 17 8 1 - 1 0 years 11 6 11 - 20 years 12 4 21 - 30 years 29 11 TOTAL 71 30 - 41 - Table I I ; CAUSES OF DEATH IN THE 101 PATIENTS: ACUTE CAUSES Trauma 22 Acute Infection 11 Suicide 9 Drowning 7 Prematurity 5 Ruptured berry aneurysm . . . . 4 Other causes 12 Total 70 CHRONIC CAUSES Malignancy 15 Congenital heart disease . . . 4 Chronic renal disease . . . . 3 Chronic i n f e c t i o n 3 Other causes 6 Total 31 - 4 2 - TABLE I I I ; CAUSES OF DEATH IN THE 0 - 1 YEAR AGE GROUP. NO. Pneumonitis 6 Pneumonitis with myocarditis 1 Pneumonitis with G.I. aspiration 2 Pneumonitis with dehydration • „t . . . . 1 Atel e c t a s i s 3 Ate l e c t a s i s ( s t i l l b o r n ) 4 A t e l e c t a s i s with cerebral hemorrhage 1 Congenital heart disease 3 Hyaline membrane disease 2 Asphyxi a 2 Pulmonary edema 1 Dehydration (post-op. Hirschprung's disease) . .. . 1 - 4_ - 1 body of the r i g h t atrium and the main pulmonary artery into the ri g h t a t r i o v e n t r i c u l a r sulcus. This e p i c a r d i a l portion of the artery was the part used. In 10% of the human hearts the r i g h t coronary artery bifurcates near i t s o r i g i n and sends a large branch coursing diagnonally across the anterior free wall of the r i g h t v e n t r i c l e (75). This artery was not used i n the study. METHODS; The removal of the proximal portion of the r i g h t coronary artery was accomplished by dissec t i o n under ao^issecting micro scope. The vessel was freed from the e p i c a r d i a l fat with gentle t r a c t i o n on the d i s t a l end. Since longitudinal sections were re quired, rather than s e r i a l sections, and as both sides were d e s i r  ed, the ar t e r i e s were prepared i n two ways depending on whether or not they had been opened at autopsy. For closed or i n t a c t vessels a % - 1 cm. cylinder was removed and bisected l o n g i t u d i n a l l y (Figure 1 A)• For vessels that had been opened, two % - 1 cm. ribbons from either side were prepared (Figure I B ) . In both cases i t was attempted, by using the dissecting microscope, to include the areas of maximum gross intimal thickening i n the part to be sectioned. The specimens were mounted i n p a r a f f i n blocks after which sections 8 microns i n thickness were made and stained both with hematoxylin and eosin, and Gomori's aldehyde-fuchsin for e l a s t i c t i s s u e . Quantitative evaluation; The microscopic measurements were made using an ocular mic rometer. - 44 - Figure 1; Diagramatic Representation of the Two Methods of Preparing the Tissue for Longitudinal Sectioning - 45 - A l l measurements were made by the author. 1. Using 10 X 10 magnification the over a l l length of the specimens was determined. 2. Using 10 X 10 or 10 X 40 magnification, depending on the size of the a r t e r i a l wall, the thickness of the intima from the i n t e r n a l e l a s t i c lamina to the endothelium was measur ed ( Figure 2 ). Measurements were taken at approximately one millimeter i n t e r v a l s . 3. At the same i n t e r v a l s the thickness of the media, from i n t e r n a l e l a s t i c lamina to adventitia was measured (Figure 2). 4. Using 10 X 40 magnification, the amount of e l a s t i c change was measured for the whole length. A s o l i d regular, wavy band was interpreted as normal. Areas of disruption, fragment ation, fraying, s p l i t t i n g and swelling were considered "change". ( Figure 2 ). Steps 1 to 4 were repeated for the second side of the artery. Of the 101 specimens, seven showed some areas of advanced atheroma. These areas have been excluded i n c a l c u l a t i n g the intimal thickness as the underlying media has been p a r t i a l l y , or i n some cases almost completely, destroyed, which would give a d i s t o r t e d picture of the intimal thickness. Since there was very l i t t l e atheroma i n the specimens, there was very l i t t l e non uniform d i s t o r t i o n due to shrinkage during f i x a t i o n . The data was analyzed by the D i g i t a l Computer to derive the equations of the best st r a i g h t l i n e approximation and the c o r r e l a t i o n c o - e f f i c i e n t s . - 46 - Figure 2 : Diagram of longitudinal section to show quantitative evaluation: A. 1 mm. i n t e r v a l measurements of intimal thickness B. 1 mm. i n t e r v a l measurements of medial thickness C. area of i n t e r n a l e l a s t i c lamina change - 47 - RESULTS : The measurements of the intimal thickness were averaged and are presented i n Table IV as "average thickness of intima" expressed i n microns. S i m i l a r l y the measurements for medial thickness are presented as "average thickness of media ". The intima has also been expressed as a percentage of the t o t a l a r t e r i a l wall (intimal thickness + medial thickness) and i s presented i n column 5 i n Table IV. The i n t e r n a l e l a s t i c lamina change i s ^expressed as a percentage of the t o t a l length used o l i the artery (column 6, Table IV )• For s t a t i s t i c a l analysis the causes of death have been divided into chronic and non-chronic diseases. These are explained i n Table I I . Since only 21 of the i n d i v i d u a l specimens had recorded blood pressures, t h i s parameter cannot be used i n analyzing the data. Figures 3 to 9 are photomicrographs to demonstrate the d i f f e r e n t aspects of the a r t e r i a l wall i n the d i f f e r e n t age groups,, studied. Figure 3 i s a hematoxylin and eosin stained preparation of a longitudinal section of the r i g h t coronary a r t e r i a l wall as seen i n most neonatal infants. This p a r t i c u l a r specimen i s from a 0.25 year o l d white female infant who died of dehydration due to acute e n t e r i t i s (specimen number A65-432). There i s a normal or i n t a c t i n t e r n a l e l a s t i c lamina underlying a th i n endothelial l i n i n g ( not demonstrated well i n the photograph). Under the i n t e r n a l e l a s t i c lamina are regular c i r c u l a r l y arranged smooth AGE SEX AVERAGE AVERAGE % INTIMA % INTERNAL WEIGHT (HEART CAUSE OF • THICKNESS OF I THICKNESS OF OF TOTAL ELASTIC (lbs) WEIGHT DEATH INTIMA (Microns MEDIA(microns) LAMINA (grams) CHANGE 6.50 M 50.57 142.04 26.11 21.80 41.50 95 CHRONIC 25.00 M 145.08 161.48 47.39 48.03 180.00 370 NON-CHRONIC 9.00 P 53.02 98.90 35.42 23.66 110 NON-CHRONIC 1.58 F 37.23 113.85 24.67 19.76 21.50 65 CHRONIC 30.00 M 41.42 125.51 24.81 85.75 550 CHRONIC 0.01 M 6.51 39.10 14.27 26.75 3.50 16 NON-CHRONIC 0.25 F 6.80 53.04 12.63 17.16 12.00 50 NON-CHRONIC 0.01 M 23.09 108.38 17.02 70.38 12.08 64 CHRONIC 1.25 M 44.88 102.00 30.55 29.82 22.00 40 CHRONIC 3.50 M 89.25 105.28 45.43 69.78 24.00 192 CHRONIC 11.00 M 37.18 110.64 24.86 21.01 150 CHRONIC 0.12 M 59.79 ' 107.64 35.38 81.82 6.62 25 CHRONIC 16.00 F 67.99 166.60 28.98 22.76 110.00 230 NON-CHRONIC 6.00 M 28.41 96.85 20.87 11.89 55.25 140 CHRONIC 0.06 F 0.00 55.25 0.00 0.27 7.34 34 CHRONIC 29.00 M 136.20 113.04 51.84 56.56 250 CHRONIC 0.00 M 0.00 10.25 0.00 0.00 2.33 7 NON-CHRONIC 27.00 M 520.50 227.40 69.63 85.15 104.00 300 CHRONIC 0.13 M 72.84 50.74 46.63 83.51 5.14 31 NON-CHRONIC 25.00 M 170.40 236.30 41.90 80.74 145.00 - 590 CHRONIC 7.00 M 37.73 83.35 31.20 49.64 50.00 140 CHRONIC 24.00 F 80.14 97.14 44.97 32.74 250 NON-CHRONIC 25.00 M 153.46 131.65 53.81 64.00 240 CHRONIC 5.50 M 55.97 122.54 30*05 57.65 47.00 190 CHRONIC 0.03 M 42.21 49.37 33.37 45.94 6.25 24 NON-CHRONIC 1.08 M 21.30 121.55 15.95 44.80 19.16 CHRONIC 0.00 F 2.67 34.73 7.08 7.90 2.95 7 NON-CHRONIC 8.00 M 74.80 189.04 27.71 59.60 80.00 190 CHRONIC 17.00 M 75.94 222.22 25.25 42.18 120.00 225. CHRONIC 21.00 F 49.30 188.12 20.76 51.99 160.00 300 NON-CHRONIC 0.08 F 50.51 31.08 61.90 100.00 4.21 8 NON-CHRONIC 4.00 M 164.40 156.70- 51.90 97.50 35.00 180 CHRONIC 16.00 M 112.47 241.03 31.79 98.00 160.00 500 CHRONIC 24.00 F 25.50 43.60 36.90 15.80 90.00 220 NON-CHRONIC 1 ArtF SF.V AVERAGE THICK AVERAGE \% INTIMA INTERNAL WEIGHT HEART CAUSE OF NESS OF INTIMA THICKNESS OF OF TOTAL ELASTIC (lbs) WEIGHT DEATH [ (Microns) MEDIA (microns )s LAMINA (grams) 1 i CHANGE % 3.50/ M 26,07 91.80 22.11 30.87% 23.00 60 CHRONIC 15.00i P 107.25 130.55 45.17 29.01 210 CHRONIC 11.00 M 103.20 165.83 35.17 78.64 90.00 NON-CHRONIC 0.25 F 22.10 87.83 20.10 20.17 NON-CHRONIC 34.00 M 224.00 187.10 54.03 35.87 185.00 450 NON-CHRONIC 1.00 F 28.05 79.04 26.02 32.43 20.00 NON-CHRONIC 27.00 M 37.12 202.02 15.66 31.86 145.00 420 NON-CHRONIC 7.00 F 11.76 83.02 12.40 7.06 65.00 NON-CHRONIC 8.00 F 18.50 100.43 15.34 12.16 70.00 123 NON-CHRONIC 21.00 M 141.67 221.56 39.00 61.85 360 NON-CHRONIC 22.00 F 49.30 136.85 26.32 34.31 125.00 270 NON-CHRONIC 33.00 F 94.17 134.98 41.01 49.653 260 NON-CHRONIC 22.00 F 34.00 133.73 19.74 37.60 135.00 NON-CHRONIC 0.67 F 23.63 75.26 24.22 24.83 20.19 NON-CHRONIC 0.12 M 52.02 139.40 25.19 94.70 7.87 37 CHRONIC 29J0O M 73.38 144.43 32.20 52.65 175.00 340 NON-CHRONIC 25.00 M 130.61 170.57 43.45 95.19 135.00 250 NON-CHRONIC 23.00 F 257.93 119.32 68.49 96.98 150.00 220 NON-CHRONIC 28.00 M 158.39 218.09 41.29 58.23 175.00 250 NON-CHRONIC 28.00 M 189.20 185.90 50.41 75.69 225.00 310 NON-CHRONIC 18.00 M 118.07 141.06 44.33 82.70 140.00 220 NON-CHRONIC 28.00 M 119.63 221.10 35.12 85.33 145.00 420 NON-CHRONIC 21.00 F 75.28 129.68 36.72 67.93 125.00 240 " NON-CHRONIC 25.00 M 67.08 125.82 34.71 43.91 170.00 250 NON-CHRONIC 30.00 M 431.40 293.48 57.50 100.00 155.00 480 CHRONIC 20.00 M 139.70 200.20 41.01 91.50 190.00 325 NON-CHRONIC 0.20 M 9.07 83.57 9.90 24.16 10.19 NON-CHRONIC 24.00 F 91.56 192.09 32.17 100.00 135.00 300 NON-CHRONIC 16.00 F 129.63 207.83 38.50 100.00 120.00 240 NON-CHRONIC 22.00 M 218.20 184.99 51.38 96.35 190.00 210 NON-CHRONIC 27.00 M 81.41 135.56 36.89 83.60 130.00 300 NON-CHRONIC 23.00 M 431.60 214.91 64.90 98.50 170.00 230 NON-CHRONIC 15.00 M 138.26 164.33 45.69 89.51 130.00 300 CHRONIC 30.00 M 257.13 157.51 61.62 92.47 180.00 450 NON-CHRONIC m H < > 9 8 > M o I—1 to M O H CO o o AGE ' SEX AVERAGE AVERAGE % INTIMA % INTERNAL -WEIGHT 1 HEART CAUSE OF i THICKNESS OF THICKNESS OF OF TOTAL ELASTIC (lbs) i WEIGHT - DEATH • INTIMA(microns) MEDIA(microns) LAMINA CHANGE (grams), 26.00 M 110.50 175.95 38.33 ' 98.09 200.00 280 NON-CHRONIC 24.00 M 145.02 308.11 32.00 100.00 165£0( \ 300 NON-CHRONIC 33.00 M 173.25 171.32 50.28 100.00 200.00, 300 NON-CHRONIC 0.71 M 0.00 82.13 0.00 0.00 15.00' 40 CHRONIC 0.00 M 13.36 32.78 28.49 45.19 3.00 10 NON-CHRONIC 3.50 F 24.58 102.91 18.89 66.91 100 CHRONIC 0.00 F 2.67 56.34 4.38 22.09 9.11 35 NON-CHRONIC 22.00 F 84.72 86.42 50.51 56.70 158.00 300 -NON-CHRONIC 0.02 M 0.74 32.55 2.22 26.71 15.93 24 NON-CHRONIC 0.00 F 0.00 36.27 0.00 0.00 6.05 50 NON-CHRONIC 18.00 M 177.95 212.71 45.31 97.50 320 NON-CHRONIC 0.00 M 0.00 38.08 0.00 8.15 6.62 18 NON-CHRONIC 0.00 F 5.51 55.25 9.17 22.83 13.93 20 NON-CHRONIC 0.17 M 0.00 70.30 0.00 10. 25 40 CHRONIC 0.00 M 2.04 52.02 3.80 35.29 20 NON-CHRONIC 21.00 M 69.20 190.83 32.59 97.50 NON-CHRONIC 20.00 M 183.33 157.91 53.67 96.55 275 CHRONIC 0.00 M 16.31 41.29 27.61 85.50 7.90 NON-CHRONIC 23.00 M 66.00 154.00 29.26 73.55 170.00 NON-CHRONIC 0.21 M 1.15 57.95 1.91 12.47 NON-CHRONIC 21.00 M 204.05 180.04 53.12 100.00 NON-CHRONIC 18.00 M 62.32 163.93 27.56 73.30 NON-CHRONIC 16.00 M 99.17 149.03 39,96 78.80 375 NON-CHRONIC 21.00 F 71.68 - 137.76 33.95 69.37 NON-CHRONIC 0.17 M 2.92 69.90 4.02 17.40 NON-CHRONIC 27.00 M 250.21 135.99 64.84 100.00 200.00 NON-CHRONIC 17.00 M 104.69 199.31 34.49 97.90 175.00 450 NON-CHRONIC 15.00 F 61.55 127.15 32.62 86.48 115.00 270 NON-CHRONIC 0.06 M 4.53 81.03 4.94 58.05 9.12 10 NON-CHRONIC 29.00 M 88.83 118.58 42.70 74.64 160.00 420 NON-CHRONIC 3.00 M 56.21 163.32 25.58 96.75 32.00 68 CHRONIC 23^00 M 132.83 188.65 41.30 80.09 145.00 250 NON-CHRONIC 0.13 M 146.94 109.08 55.96 78.72 NON-CHRONIC - 51 - muscle c e l l s of the media- This i s an example of the "normal" wall of a muscular artery. Figure 4 i s the same specimen as figure 3 stained for e l a s t i c t i s s u e with aldehyde fuchsin. This photograph demon strates better the normal i n t e r n a l e l a s t i c lamina. Scattered e l a s t i c f i b e r s are seen also i n the media and adventitia. The average intimal thickness i n t h i s specimen i s 7 microns, and the average medial thickness i s 53 microns. Figure 5 i s a longitudinal section, stained with alde hyde fuchsin, of the r i g h t coronary a r t e r i a l wall i n a two year old white male who died from acute b l a s t c e l l leukemia (specimen number A65-431). There i s a minimal p r o l i f e r a t i o n of connective tissue elements between the endothelium and the i n t e r n a l e l a s t i c lamina, which shows only minimal change. The i n t e r n a l e l a s t i c lamina shows evidence of s p l i t t i n g i n the upper r i g h t corner with two d e f i n i t e breaks i n the central area, under the area of maxi mal intimal hyperplasia. The intima shows evidence of e l a s t i c neogenesis and a longitudinal arrangement of the f i b e r s . In t h i s specimen the average intimal thickness i s 37 microns, the average medial thickness i s 114 microns, and the average change of the i n t e r n a l e l a s t i c lamina i s 19% of the t o t a l length. Figure 6 i s a longitudinal section, stained with hematoxy l i n and eosin, of the r i g h t coronary a r t e r i a l wall i n a 25 year old white male who died of a ruptured berry aneurysm (specimen number A65-409). There i s a moderate amount of intimal hyper p l a s i a . The average thickness of the intima i s 145 microns and the average thickness of the media i s 161 microns. F i g u r e 3. An i n t a c t i n t e r n a l e l a s t i c lamina overlying the media composed of regularly c i r c u l a r l y arranged smooth muscle c e l l s . Longitudinal section. Paraffin, H & E-, 50 X. - 53 - Figure 5. Early intimal hyperplasia, most marked over the area of most in t e r n a l e l a s t i c lamina change. Note the gaps and area of fraying of the in t e r n a l e l a s t i c lamina, and the e l a s t i c neogenesis i n the intima. Longitudinal section, Paraffin, Aldehyde, Fuchsin, 50 X. - 54 - T h i s photograph demonstrates w e l l , the r e o r i e n t a t i o n o f the smooth muscle c e l l s which a r e l o n g i t u d i n a l l y arranged i n the i n t i m a . The i n t e r n a l e l a s t i c lamina demonstrates a moderate degree o f change. F i g u r e 7 i s t h e same specimen as F i g u r e 6 s t a i n e d w i t h aldehyde f u c h s i n . The s i t e i s not e x a c t l y the same, as the l a r g e break i n the i n t e r n a l e l a s t i c lamina seen i n the c e n t r e o f the hematoxylin and e o s i n p r e p a r a t i o n i s on the r i g h t i n t h i s photo graph. T h i s photograph demonstrates more c l e a r l y a moderate degree o f change i n the i n t e r n a l e l a s t i c l amina. There are two l a r g e gaps p r e s e n t . The average change from the normal o f the i n t e r n a l e l a s t i c lamina i n t h i s specimen i s 48% o f the t o t a l l e n g t h . F i g u r e s 8 and 9 a r e both examples o f a l a r g e amount o f i n t i m a l h y p e r p l a s i a and a l a r g e degree o f i n t e r n a l e l a s t i c lamina change. Both are l o n g i t u d i n a l s e c t i o n s o f the r i g h t coronary a r t e r y s t a i n e d w i t h aldehyde f u c h s i n . F i g u r e 8 i s a fo u r year o l d white male who d i e d f o l l o w  i n g open h e a r t surgery f o r r e p a i r o f an i n t e r v e n t r i c u l a r s e p t a l d e f e c t (specimen number A65-434). The average i n t i m a l t h i c k n e s s i s 164 microns. The average medial t h i c k n e s s i s 156 microns. There a r e o n l y fragments o f normal i n t e r n a l e l a s t i c lamina remaining i n the specimen. F i g u r e 9 i s a 20 year o l d white male who d i e d o f c e r e b r a l trauma (specimen number 65-809). The average i n t i m a l t h i c k n e s s i s 154 microns. The average medial t h i c k n e s s i s 200 microns. - 55 - Figure 6. A moderate amount of intimal thickening i s seen over an i n t e r n a l e l a s t i c lamina which demonstrates large gaps. Note the l o n g i t u d i n a l l y arranged smooth muscle c e l l s , e s p e c i a l l y i n the basal part of the intimal layer. Longitudinal section, Paraffin, H. & E.,50 X. Figure 7. Same specimen as figure 6. Longitudinal section, Paraffin, Aldehyde Fuchsin, 50 X. - 56 - There i s no normal i n t e r n a l e l a s t i c lamina remaining i n the specimen. Although t h i s series of seven examples does not conform to the rela t i o n s h i p s found i n regard to intimal thickness vs. age, and i n t e r n a l e l a s t i c lamina change vs. age, as shown i n Figures 11, and 16, they do i l l u s t r a t e the r e l a t i o n s h i p of intimal hyperplasia vs. i n t e r n a l e l a s t i c lamina change as shown i n Figures -13, and 14, and 15. Figure 5 demonstrates an i n t e r e s t i n g observation which was noted i n specimens where the intimal thickness was minimal and somewhat i r r e g u l a r . In these specimens the maximum intimal thickness almost always.occurred over the areas of greatest i n  ter n a l e l a s t i c lamina change. Because of the r e l a t i v e l y few spec imens i n t h i s category, no s t a t i s t i c a l c o r r e l a t i o n was attempted. Also, the r a t i o of c e l l u l a r to e x t r a c e l l u l a r material was noted to be higher i n the early lesions when compared to l a t e r ones. The q u a l i t a t i v e and quantitative r e s u l t s of Table IV are presented i n graphic and tabular form i n the suceeding pages. Figure 10 i s a graph of the 101 observations obtained for the absolute thickness of the intima i n microns, on the Y axis, compared to the age i n years, on the X axis. The equation of the best straight l i n e approximation i s : Y = -89.88 + 13.25X. This l i n e does not pass through the o r i g i n of a d i s t o r t i o n r e s u l t i n g from three very large values for the intimal thickness. These are the three values at the top of the graph which range between 431 and 520 microns. However, from the spread of points on the graph i t i s evident that - 57 - Figure 8. There i s a thick intimal layer with only remnants of the i n t e r n a l e l a s t i c lamina remaining between i t and the medial layer. Note the e l a s t i c neogenesis i n the base of the intima. Longitudinal section, P a r a f f i n , Aldehyde Fuchsin, 50 X. Figure 9. There i s a thick intimal layer with no i n t e r n a l e l a s t i c lamina remaining. The boundary between the intimal and medial layers i s taken as the zone of reorientation of the f i b e r s which i s c l e a r l y seen here. Longitudinal section, Paraffin, Aldehyde Fuchsin,50 X. - 58 - there i s c o r r e l a t i o n between these two variables. The c o r r e l a  t i o n c o - e f f i c i e n t r i s 0.61 (p<.01, error df 99). There i s , therefore a highly s i g n i f i c a n t c o r r e l a t i o n between these two variables. Figure 11 i s a graph of the absolute thickness of the intima, on the Y axis, compared to the age i n years, on the X axis, for patients dying of non-chronic causes (70 observations). I t i s evident from the graph that there i s a s i m i l a r r e l a t i o n s h i p as for Figure 10. Although only a l i n e a r regression was calcu lated for Figure 10, both these graphs suggest that higher powers should be employed to obtain a more accurate approximation to the data, which would therefore give an even better c o r r e l a t i o n co e f f i c i e n t . An approximation of t h i s i s superimposed on Figure 11. Figure 12 i s a graph of the r e l a t i v e thickness of the intima, on the Y axis, (intima expressed as a percentage of the t o t a l thickness of the a r t e r i a l wall) compared to the age i n years, on the X axis (101 observations). This does not correlate as well as figure 10 due to the a r t i f i c i a l l y high values i n the infants where any intimal thickness i s magnified on a r e l a t i v e scale due to the thinness of the media i n t h i s age group. In Table V, the specimens are divided into three arb i t r a r y age groups; 0-2, 1-15, & 16-30 years. The average intimal t h i c k  ness i n each .group i s compared using a paired sample "T" t e s t . From t h i s table i t i s seen that there i s a highly s i g n i f i c a n t difference between the three age groups. This i s additional proof that the intimal thickness does increase with age. A G E ( Y E A R S ; 2.80- NON CHRONIC DISEASE a oo-l O < I— 12-Oi 8 0 1 40H 20" 6 ifU ) £ 3 ? ¥~~Z T~l 5~lc IO 1 5 - ACE (YEARS) Z5 30 2] c n o I N T I M A { < O P T O T A L W A L L ) - T9 ~ - 62 - TABLE V« Comparison of int i m a l hyperplasia i n three age groups, (sexes combined) AGE AVERAGE INTIMAL THICKNESS (u) CALCULATED STUDENT* S T ' SIGNIFICANCE c<= .05 0-2 17.09 t= '4.811 s i g n i f i c a n t 1-15 57.72 df 51 difference p<.001 1-15 16-30 57.72 140.24 t= 3.713 df 71 s i g n i f i c a n t difference p < .001 TABLE VI. Comparison of intimal hyperplasia i n three age groups. (Males) AGE SAMPLE AVERAGE INTIMAL CALCULATED SIGNIFICANCE SIZE THICKNESS (u) STUDENT'S T o C = .05 0-2 20 18.64 t=6.456 s i g n i f i c a n t difference 1-15 14 66.28 df32 p < .001 1-15 14 66.28 t=3.353 s i g n i f i c a n t difference 16-3C 38 158.29 df50 P < .01 - 63 - TABLE VII. Comparison of intimal hyperplasia i n three age groups. (Females AGE SAMPLE AVERAGE INTIMAL CALCULATED SIGNIFICANCE SIZE THICKNESS (u) STUDENT* S T oC = .05 0-2 10 15.71 t=2.320 s i g n i f i c a n t difference 1-15 8 42.74 df 16 .01<p <.05 1-15 8 42.74 t=1.890 no s i g n i f i c a n t 16-30 13 85.41 df 19 difference • 05<p <.10 In tables VI and VII the three age groups are divided into males females. Table VI demonstrates that i n males there i s s t i l l a highly s i g n i f i c a n t difference between the three groups. However, i n table VII i t i s seen that while there i s i n females a s i g n i f i c a n t d i f f e r  ence at the 95% l e v e l between the 0-2 and the 1-15 year age groups, there i s not a s i g n i f i c a n t difference between the 1-15 and 16-30 year age groups. This may be a r e f l e c t i o n of the smaller sample sizes i n the female groups. I f these same three groups are used to compare differences i n int i m a l thickness between the sexes, i t i s seen i n table VIII that no s i g n i f i c a n t difference e x i s t s between the males and females i n the 0-2 and 1-15 year age_groups but that there i s a s i g n i f i c a n t difference i n the 16-30 year age groups. Again t h i s may be a r e f l e c  t i o n of sample siz e as there are very few females i n the 16-30 age groups compared to the number of males. TABLE VIII. Comparison of in t i m a l thickness i n male and female. AGE INTIMAL THICKNESS (AV.) CALCULATED STUDENT * S T SIGNIFICANCE o C - .05 MALE FEMALE 0-2 18.64 15.71 t=0.350 df 28 no s i g n i f i c a n t difference p <.05 1-15 66.28 42.74 t=1.348 df 20 no s i g n i f i c a n t difference .20<p<. 30 16-30 158.99 85.41 t=2.373 df 49 s i g n i f i c a n t difference .02< p < .05 - 64 - Figure 13 i s a graph of the absolute thickness of the intima, on the Y axis, compared with the i n t e r n a l e l a s t i c lamina change, on the X axis (101^ observations). The equation of the best straight l i n e approximation i s : Y=8.07+1.40 X. The c o r r e l a t i o n c o e f f i c  i ent r i s 0.49 (p<.01, error <df 99J. There i s therefore, s i g n i  f i c a n t c o r r e l a t i o n between these two var i a b l e s . Figure 14 i s the same as figure 13 but uses only data from patients dying of non-chronic disease. The regression and corre l a t i o n have not been calculated but i t i s evident from the graph that c o r r e l a t i o n i s at l e a s t as good as that of figure 13. There are r e l a t i v e l y fewer specimens with a small intimal thickness and a high degree of i n t e r n a l e l a s t i c lamina change, which suggests that perhaps disease processes do have some e f f e c t on the e l a s t i c changes. Figure 15 i s a graph of the r e l a t i v e i n timal thickness, on the Y axis, compared to the amount of i n t e r n a l e l a s t i c lamina change, on the X axis (101 observations). This r e l a t i o n s h i p i s used as well as that of figure 13 because t h i s i s a comparison of two r e l a t i v e e f f e c t s of tissu e change. The equation of the best s t r a i g h t l i n e approximation i s : Y=11.75+0.35 X. The c o r r e l a t i o n c o e f f i c i e n t r i s 0.66 (p<-01, error df 99). This i s a highly s i g n i f i c a n t c o r r e l a t i o n between these two var i a b l e s . I t i s much better than that i n figure 13. Figure 16 i s a graph of the amount of i n t e r n a l e l a s t i c lamina change, on the Y axis, compared to the age i n years, on the X axis (101 observations). The equation of the best straight l i n e y - I N T I M A X - I, E . L . C H A N C E " y=8.07 + I.40X- o -t—* 1 • 7 _ 1 i i i i IO ZO 3 0 4 0 J O 6 0 7 0 8 0 90 10 INTERNA E L A S T I C LAMINA CHANGE (%) 280- 240- N O N C H R O N I C D I S E A S E " o c J] n 1 + zoo] 160 cn cn vr> iz.o -I -z. O or VJ 80 60 4-oH 2,0 H 10 2.0 3o 4 0 5"0 6 0 7 0 I N T E R N A L E L A S T I C L A M I N A C H A N G E ( % ) BO 90 loo - 67 - F I G U R E 15" S K * ( ~ n v M I V _ L O _ L J O °/P) \m\±.u\ s UJ o z < X 8 0 - u < < 60- - J u r- • < Lu _ J < _ DC L J 2.0- h y - I . E . L . C H A N G E X = A G E « 1 1 1 T r 1 1 1 1 P r — r — i 1 1 1 1 1 i 1 1 , i i 1 1 1 1 1 1 1 i i ° 2 4 ^ I Z- 3 f 5" 6 7 & 9 IO IS ZO 25 30 A C E ( y E A R S ) - 69 - approximation i s : Y=10.01+1.40 X. The c o r r e l a t i o n c o e f f i c i e n t r i s 0.49 (p<.01, e r r o r d f 99). Although t h i s i s a s i g n i f i c a n t c o r r e l a t i o n , i t i s not as h i g h as some o f the oth e r c o r r e l a t i o n s . T h i s i s the r e s u l t o f a low c o r r e l a t i o n i n the younger age groups, as seen i n f i g u r e 16. TABLE IX. COMPARISON OF THE AVERAGE % INTERNAL ELASTIC LAMINA CHANGE IN THREE AGE GROUPS. (SEXES COMBINED) AGE SAMPLE AVERAGE % CALCULATED' SIGNIFICANCE SIZE I.E.L. CHANGE STUDENT'S T °C = .05 0-1 28 36.44 t=1.303 no s i g n i f i c a n t 1-15 22 47.12 d f 48 d i f f e r e n c e . 10<p<.20 1-15 22 47.12 t=4.229 s i g n i f i c a n t d i f f e r e n c e 16-30 51 73.53 d f 71 p <.001 I t i s seen from t a b l e IX t h a t t h e r e i s s i g n i f i c a n t d i f f e r  ence i n the average percentage i n t e r n a l e l a s t i c lamina change o n l y between the 1-15 and 16-30 year age groups. S i m i l a r r e s u l t s t o t a b l e IX are o b t a i n e d i f males and females are compared s e p a r a t e l y . Table X compares the d i f f e r e n c e s i n the sexes i n the t h r e e age groups, w i t h r e s p e c t t o the amount o f i n t e r n a l e l a s t i c lamina change. The o n l y s i g n i f i c a n t d i f f e r e n c e o ccurs i n the 16 - 30 year age group. - 70 - TABLE X. COMPARISON OF THE SEX DIFFERENCES IN THE AVERAGE INTERNAL ELASTIC LAMINA CHANGE IN THREE AGE GROUPS. AGE , SEX CALCULATED STUDENT'S T SIGNIFICANCE o c = .05 MALE SAMPLE SIZE FEMALE SAMPLE SIZE 0-1 42.73 19 23.92 9 t=1.458 d f 26 no s i g n i f i c a n t d i f f e r e n c e . 10<p<.20 1-15 54.23 14 34.68 8 t=1.941 d f 20 no s i g n i f i c a n t d i f f e r e n c e .05<p<.10 16-30 79.32 38 56.60 13 t=3.106 d f 49 s i g n i f i c a n t d i f f e r e n c e ~.001<p<.10 F i g u r e 17 i s a graph o f the a b s o l u t e t h i c k n e s s o f the media, on the Y a x i s , compared to the age i n ye a r s , on the X a x i s , (101 o b s e r v a t i o n s ) . The equation o f the b e s t s t r a i g h t l i n e approximat i o n i s : Y = 23.45 + 7.89 X. Hie c o r r e l a t i o n c o e f f i c i e n t r i s 0.69 (p<-01, e r r o r d f 99). T h i s i s a h i g h l y s i g n i f i c a n t c o r r e l a t i o n between these two v a r i a b l e s . F i g u r e 18 i s a graph of the a b s o l u t e t h i c k n e s s o f the in t i m a , on the Y a x i s , compared t o the a b s o l u t e t h i c k n e s s o f the media, on the X a x i s . The equation o f the b e s t s t r a i g h t l i n e approximation i s Y = -40.46 + 0.10 X. The c o r r e l a t i o n c o e f f i c i e n t r i s 0.67 (p<.01, e r r o r d f 99), which i s h i g h l y s i g n i f i c a n t . Since the graph suggests an i n c r e a s i n g s l o p e w i t h i n c r e a s i n g medial t h i c k n e s s , i n order t o determine i f the i n t i m a i s grow i n g a t a more r a p i d r a t e than the media, a l o g a r i t h m i c t r a n s  f o r m a t i o n was done on the data and a r e g r e s s i o n c a l c u l a t e d on t h i s . U s i n g Y = l o g . i n t i m a l t h i c k n e s s , X = l o g . medial t h i c k n e s s , the equation o f the b e s t s t r a i g h t l i n e approximation i s : Y = -5.06 + 1.89 X. The c o r r e l a t i o n c o e f f i c i e n t r i s 0.76, which FIGURE 17 - 71 - (SNObDIlN) VI03I/N FIGURE 18 - 72 - MEDIA (MICRONS) - 73 - i s h i g h l y s i g n i f i c a n t . S i n c e the s l o p e o f a l o g a r i t h m i c t r a n s f o r m a t i o n o f Y on X i s g r e a t e r than 1, t h i s i s c o n c l u s i v e evidence t h a t i n t h i s s e t o f data the i n t i m a l t h i c k n e s s i s i n c r e a s i n g a t a more r a p i d r a t e than the medial t h i c k n e s s . F i g u r e 19 i s a graph o f the a b s o l u t e i n t i m a l t h i c k n e s s , on the Y a x i s , compared t o the h e a r t weight, on the x a x i s (83 o b s e r v a t i o n s ) . The e q u a t i o n o f the b e s t s t r a i g h t l i n e approximation i s : Y = 20.66 + 0.35 X. The c o r r e l a t i o n c o e f f i c i e n t r i s 0.55 (p < .01, e r r o r d f 81), which i s s i g n i f i c a n t . F i g u r e 20 i s a graph o f the a b s o l u t e i n t i m a l t h i c k n e s s on the Y a x i s , compared t o the body weight, on the x a x i s (78 o b s e r v a t i o n s ) . The e q u a t i o n o f the b e s t s t r a i g h t l i n e approximation i s : Y - 15.23 + 0.83 X. The c o r r e l a t i o n c o e f f i c i e n t r i s 0.60 (p< .01, e r r o r d f 76), which i s h i g h l y s i g n i f i c a n t . I f a l o g a r i t h m i c t r a n s f o r m a t i o n i s performed on t h i s date, a r e g r e s s i o n o f l o g . Y on l o g . X w i l l r e s u l t i n a s l o p e g r e a t e r than 1. T h e r e f o r e the r a t e o f i n t i m a l growth i s f a s t e r than the r a t e o f growth f o r the t o t a l body mass. F i g u r e 21 i s a graph o f the degree of i n t e r n a l e l a s t i c lamina change, on the Y a x i s , compared t o the body mass, on the X a x i s . I t i s e v i d e n t from t h i s graph t h a t t h e r e i s a v e r y low c o r r e l a t i o n between these two v a r i a b l e s * T h i s i s e s p e c i a l l y t r u e i n i n f a n t s weighing l e s s than t w e n t y - f i v e pounds where t h e r e i s a g r e a t v a r i a t i o n i n the amount o f i n t e r n a l e l a s t i c lamina change. A comparison was made i n the 20-30 year age group where £ 8 0 24-0 H ZOO '—» 1 6 0 - 0 £r 1 2 0 - ^ — - < 2 so - 6 C - J . V - I N T I M A X - H E A R T W E I G H T V- Z0..66 ^-0.35X- * • * * • * 50 I O O I E T O eoo 2 5 0 • 3 0 0 H E A R T W E I G H T ( G R A M S ) 35"0 • < J - 0 0 4 - 5 0 sroo T O c 33 n F I G U R E 2 . 0 - 75 -F I G U R E Z\ - 76 - 1001 90 80 H LU r a h- < -J U J I— 30 2.0 10 2 5" 5 0 75 ' O O LZ.5- 1 5 0 1 7 5 2 0 0 BODY W E I G H T ( POUNDS) - l i  the 20 specimens w i t h the g r e a t e s t h y p e r p l a s i a were compared w i t h the 20 specimens w i t h the l e a s t h y p e r p l a s i a t o endeavour t o f i n d a c o r r e l a t i o n . The same c o r r e l a t i o n s w i t h r e g a r d t o sex, h e a r t weight, and body weight, t h a t have been d i s c u s s e d were found. T h i r t y p e r c e n t o f the group w i t h the g r e a t e s t h y p e r p l a s i a d i e d from c h r o n i c d i s e a s e compared t o o n l y t e n p e r c e n t o f the group w i t h the l e a s t h y p e r p l a s i a . T h i s d i f f e r e n c e i s 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 and c o u l d be j u s t due t o chance. - 78 - CONCLUSIONS AND DISCUSSION: From f i g u r e s 10-12 and t a b l e s V-VII i t i s shown t h a t the i n t i m a l l a y e r o f the coronary a r t e r y c o r r e l a t e s v e r y c l o s e l y w i t h age i n the 0-30 y e a r range s t u d i e d . Although the p r e s e n t a t i o n o f data suggests a d i r e c t r e l a t i o n s h i p , i t i s understood t h a t age i t s e l f i s not n e c e s s a r i l y a f a c t o r r e s p o n s i b l e f o r i n t i m a l growth but t h a t t h e r e are one or many f a c t o r s which are o p e r a t i n g e i t h e r c o n t i n u o u s l y o r i n t e r m i t t e n t l y throughout t h i s age p e r i o d t o s t i m u l a t e i n t i m a l h y p e r p l a s i a . C o n t r a r y t o Dock's (37) and Lober's (91) f i n d i n g s , no s i g n i f i c a n t d i f f e r e n c e i n the i n t i m a l t h i c k n e s s i n males and females was found under the age o f 15 y e a r s . But, t h e r e was shown t o be a d i f f e r e n c e i n the age group from 16-30 y e a r s where the i n t i m a i n the male i s g r e a t e r than t h a t o f the female. T h i s i s shown i n t a b l e V I I , and suggests t h a t some d i f f e r e n c e o p e r a t i n g a t and a f t e r p uberty has an i n f l u e n c e e i t h e r on s t i m u l a t i n g the male or i n h i b i t i n g the female i n t i m a l growth. Apart from the d i e t a r y and a c t i v i t y d i f f e r e n c e s i n the two sexes, the hormonal d i f f e r e n c e has been suggested as an i n f l u e n c i n g f a c t o r . Do the e s t r o g e n i c hormones, w i t h a p r o l i f e r a t i v e e f f e c t on e p i t h e l i a l t i s s u e but not so much on mesenchymal t i s s u e , have a r e l a t i v e r e t a r d i n g e f f e c t on the i n t i m a l growth? A c t u a l l y , l i t t l e i s known about the i n f l u e n c e o f sex hormones on human c o n n e c t i v e t i s s u e . The e s t r o g e n s w i l l i n c r e a s e the amount o f mucopolysaccharides, p a r t i c u l a r l y h y a l u r o n i c a c i d content, i n a l l c o n n e c t i v e t i s s u e . - 79 - But, Testosterone, as w e l l as s t i m u l a t i n g muscle growth and mesen chymal t i s s u e , a l s o i n c r e a s e s mucopolysaccharides s e n s i t i v e t o h y a l u r o n i d a s e (10). Since c o n n e c t i v e t i s s u e changes are o f t e n m a n i f e s t a t i o n s o f hyper or h y p o f u n c t i o n o f the hormones, i t i s c o n c e i v a b l e t h a t a sudden change i n the hormonal content, which o c c u r s a t puberty, c o u l d upset the metabolism o f the a r t e r i a l w a l l . Lober (91) c l a i m s t h a t t h e r e i s a sex d i f f e r e n c e b e f o r e puberty, b u t t h a t a f t e r the age o f t e n y e a r s the r a t e o f p r o g r e s s i o n o f male and female i n t i m a e are the same, and f o r t h i s reason he s t a t e s t h a t the hormonal d i f f e r e n c e s are not fundamental. I n h i s study he i n v e s t i g a t e d a l s o t h e p o s t menopausal p e r i o d and found t h a t the hormonal change here a l s o d i d not a p p r e c i a b l y e f f e c t the i n t i m a l t h i c k n e s s . From f i g u r e s 13 - 15 i t i s shown t h a t the i n t i m a l t h i c k n e s s i s d i r e c t l y p r o p o r t i o n a l t o the amount o f d e s t r u c t i o n o f the i n t e r n a l e l a s t i c lamina, u s i n g both the a b s o l u t e and r e l a t i v e t h i c k n e s s o f the i n t i m a . I f we accept the theory t h a t the i n t e r n a l e l a s t i c lamina i s the s i t e o f the f i r s t i n j u r y , and t h a t the i n t i m a i s a b i o l o g i c a l e x p r e s s i o n o f r e g e n e r a t i o n i n response t o the degeneration o f the i n t e r n a l e l a s t i c lamina, t h i s c o r r e l a t i o n between i n t i m a l h y p e r p l a s i a and t h e amount o f d e s t r u c t i o n o f the i n t e r n a l e l a s t i c lamina i s expected. A l s o , i t has been shown e x p e r i m e n t a l l y t h a t a f t e r i n j u r y t o the i n t e r n a l e l a s t i c lamina (or a r t e r i a l w a l l ) by v a r i o u s chemical and p h y s i c a l agents t h e r e f o l l o w s a r e p a r a t i v e i n t i m a l p r o l i f e r a t i o n (15, 29, 67, 79, 80, 118, 140, 147, 160). Ther e f o r e , t h i s i s pro b a b l y a t r u e cause - 80 - and e f f e c t c o r r e l a t i o n : t h a t i s , i n t e r n a l e l a s t i c lamina change i s the primary event i n the p r o c e s s o f i n t i m a l h y p e r p l a s i a . Supporting t h i s statement i s the f a c t t h a t i n t h i s study t h e r e i s b e t t e r c o r r e l a t i o n o f the amount o f i n t i m a l t h i c k n e s s w i t h the amount o f i n t e r n a l e l a s t i c lamina change than the c o r r e l a t i o n between t h e . i n t i m a l t h i c k n e s s and the age. S i m i l a r l y , t h e r e would be expected a r e l a t i o n s h i p between age and the amount o f i n t e r n a l e l a s t i c lamina d e s t r u c t i o n . F i g u r e 16 and t a b l e IX demonstrate 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 i n c r e a s e i n the change from the normal o f the i n t e r n a l e l a s t i c lamina w i t h i n c r e a s i n g age from one year t o 30 y e a r s . In the age group 0-12 months t h i s i s not so i n the p r e s e n t study. Here 8/26 o f the b a b i e s dying i n the f i r s t two weeks showed i n t e r n a l e l a s t i c lamina change g r e a t e r than 50% which produces a non s i g n i f i c a n t d i f f e r e n c e f o r t h i s age group. T h i s i s c a r r i e d over somewhat i n t o the 1-15 year age p e r i o d (see t a b l e V I I I ) . T h i s i s a r e f l e c t i o n o f the type o f specimen used. I n the age group over f i v e y e a r s most o f the p a t i e n t s c o u l d be c o n s i d e r e d normal from the f a c t t h a t they d i e d from t r a u m a t i c or acute causes. However, many o f the i n f a n t s d i e d from d i s e a s e p r o c e s s e s which are p r e s e n t from, or even b e f o r e , b i r t h . D i s t u r b a n c e s i n t h i s p e r i o d a f f e c t many t i s s u e s i n c l u d i n g p o s s i b l y the e l a s t i c t i s s u e . These m e t a b o l i c upsets may cause l a r g e amounts o f i n t e r n a l e l a s t i c lamina d e s t r u c t i o n which, i n oth e r people, may take up t o t h i r t y y e a r s t o produce. T h i s suggests t h a t perhaps some m e t a b o l i c p o i s o n i s p r e s e n t i n h i g h c o n c e n t r a t i o n s i n these d i s e a s e d - 81 - infants, which may injure e l a s t i c tissue r a p i d l y here, but takes much longer i n r e l a t i v e l y healthy i n d i v i d u a l s . Although t h i s metabolic factor i s unknown i t may act s i m i l a r l y to known meta b o l i c i n j u r i o u s factors such as the lathyrus factor, B- aminoproprionitrile, which attacks connective tissue by block ing the production of collagen from the f i b r o b l a s t . This i s due to a disturbance i n mucopolysaccharide metabolism, possibly as a r e s u l t of depolymerization of the ground substance (chondroi- t i n s u l f u r i c acid) which can cause an "injury" to the a r t e r i a l wall (141). In t h i s study there was found a sex difference i n the amount of i n t e r n a l e l a s t i c lamina destruction i n the age group 16-30 years (males greater than females) but not i n the younger groups (table X). This i s more evidence supporting a hormonal influence at the pubertal period. Figure 17 confirms e a r l i e r studies ((91) that the growth of the media continues with age, plateauing o f f at the 20-30 year age period, suggesting a pattern s i m i l a r to general body growth. When comparing intimal thickness with medial thickness i t i s shown that there i s a c e r t a i n p a r a l l e l i s m between the two, but, i t a logarithmic transformation i s done, i t i s shown that the intima increases at a more ra p i d rate than the media. (The equation of the slope b for log. Y on log. X i s : Y = 1.89 X.) Following on t h i s , i f the media conforms to generaly body growth, then the intima i s growing faster than general body growth, and therefore i s an abnormal or non-physiological process. - 82 - Similarly, Figures 19 and 20 show the r e l a t i o n s h i p of intimal growth to heart mass and body mass respe c t i v e l y . Employ ing a logarithmic transformation on these graphs also proves a faster rate of growth of the intima than the heart.or body mass. In t h i s study i t i s not possible to derive similar conclusions, as the above, for the i n t e r n a l e l a s t i c lamina (figure 21). In order to c l a r i f y some of the findings of t h i s paper, i t would be necessary to further investigate the infants by ob t a i n i n g a large sample of normal specimens to compare with ones with disease processes. Since invivo measurements are, at present, impossible, and because of the nature of infant mort a l i t y , t h i s would require a long period of specimen c o l l e c t i o n . Also, since some i n t e r n a l e l a s t i c lamina change i s seen at b i r t h , perhaps some work should be done on the i n t r a - u t e r i n e period of growth. From experimental work on injurious agents, and suggest ions from studies l i k e the present one, that perhaps some meta b o l i c agent i s acting along with, or instead of, a s t r i c t l y mechan i c a l factor of etiology, further search for the possible agent(s) must be done. Tnere are many inj u r i o u s agents which have been used experimentally i n animals, but somehow these agents must be t i e d i n t o human intimal hyperplasia. Perhaps some metabolic factor from the diseased infants, which suggested such a mater i a l , could be used to promote animal intimal hyperplasia, as the reverse i s not possible. A c a r e f u l study of a series of cases might give clues to such metabolic conditions and t h e i r possible - 33 - e f f e c t s on the i n t e r n a l e l a s t i c lamina. i n the present study the diseases i n the infant group were very variable (table III) but, with a large percentage of respiratory problems. 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