Histologic changes in the normal aging aorta: Implications for dissecting aortic aneurysm

Histologic Changes in the Normal Aging Aorta: Implications for Dissecting Aortic Aneurysm

THOMAS J. M. SCHLATMANN, MD ANTON E. BECKER, MD, FACC

Amsterdam, The Netherlands

The histologlc changes that occur in the media of the normal aorta at various ages were studied in 100 normal aortas. These changes encorepassed (1) cystic medial necrosis, defined as pooling of mucoid material; (2) elastin fragmentation, characterized by disruption of elastin lamellae; (3) fibrosis, defined as an Increase in collagen at the expense of smooth muscle cells;and (4) medionecrosis, defined as areas with apparent loss of nuclei. The changes showed a striking correlation with age and may represent the normal aging process for the aorta as determined histologically. The alterations showed a close relation in onset and location within the media, suggesting a phenomenon of injury and repair caused by hemodynamic events. These findings in the normal aging aorta reveal that none of the histologic changes observed can be regarded as the specific structural alteration responsible for the development of dissecting aneurysm.

Although little is known of the histologic changes t h a t occur in the media of the aorta with increasing age 1-3 this information is i m p o r t a n t because some previously r e p o r t e d changes have also b e e n implicated in the pathogenesis of dissecting a n e u r y s m . Medionecrosis, 4-7 cystic medial necrosis 3,8-1° a n d f r a g m e n t a t i o n of elastin fibers TM each have been n a m e d in this respect. In this s t u d y we e x a m i n e d the changing histopathologic features of the n o r m a l aortic m e d i a at various ages, in order to establish an overall view of the m e d i a in the aging a o r t a as reference for f u r t h e r studies of pathologic specimens. Material and Methods

From the Department of Pathology,University of Amsterdam, Wilhelmina Gasthuis, Amsterdam, The Netherlands.Manuscript received August 5, 1976; accepted September 14, 1976. Address for reprints: Anton E. Becker, MD, Department of Pathology, Wilhelmina Gasthuis, Eerste Helmersstraat 104, Amsterdam, The Netherlands.

Cases: The study material comprised 100 aortas selected from patients who did not manifest aneurysmal dilatation of the ascending aorta or complete or incomplete varieties of dissecting aneurysm. The patients were selected so that 20 were studied from each of the following age groups: 0 to 19, 20 to 39, 40 to 59, 60 to 79 and 80 years and more. There were 61 male and 39 female subjects. Retrospective application of the criteria of Hirst et al. 12 revealed 22 patients who would have been considered to have hypertension; 20 in this group were more than 40 years old and the remaining 2 were 36 and 39 years old, respectively. Histology: All the aortas were fixed in a solution of 4 percent formaldehyde. Blocks for histologic study covering the total aortic circumference were taken from the following sites: (1) 2 cm above the aortic ostium, (2) from the aortic a r c h between the origin of the left common carotid artery and the left subclavian artery, (3) at the level of the diaphragm, and (4) from the abdominal aorta at a level halfway between the renal arteries and the aortic bifurcation. The blocks were sectioned at 7 ~ thickness, and the sections were stained with hematoxylin-eosin, elastic tissue stain, periodic acid-Schiff stain, alcian blue stain and combinations of the alcian blue technique with either the period acid-Schiff or the van Gieson stain. The inclusion in the study of aortas with atherosclerosis was unavoidable. Because the intimal lesions of atherosclerosis have a pronounced effect on the media, 13we always attempted to take sections from unaffected sites. In patients older than 60 years, this was frequently not possible, particularly with regard to the sections taken from the abdominal aorta.

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NORMAL AGING AORTA--SCHLATMANN AND BECKER

Basic Pattern of the Aortic Media Four basic ingredients constitute the aortic media: (1) elastin fibers, (2) collagen fibers, (3) smooth muscle cells, and (4) an amorphous ground substance, rich in acid mucopolysaccharides. These components are arranged in orderly periluminal lamellar units. 14-17 Each unit is composed of two parallel elastin fibers, with smooth muscle cells, collagen fibers and ground substance sandwiched between. Tiny elastin fibers traverse the unit and interconnect in part the two major elastin lamellae. This basic pattern is present throughout the total length Of the aorta, although there are both qualitative and quantitative differences between the thoracic and abdominal segments, is Thoracic versus abdominal a o r t a : Particularly interesting is the described difference is between the normal increase in medial thickness after birth in the thoracic and in the abdominal segments. In the thoracic segment this is mainly accomplished by an increase in the number of lamellar units (from 35 to 56), whereas the thickness per unit shows only a minor increase (from 0.012 to 0.017 ram). In the abdominal segment, the situation is reversed; the number of lamellar units increases minimally (from 25 to 28), whereas the individual thickness of the units increases significantly (from 0.012 to 0.026 ram). This increase is mostly due to a proliferation of smooth muscle cells. It follows that the stress exerted on separate lameUar units is greater in the abdominal than in the thoracic segment, particularly since the pulse pressure in the abdominal aorta is believed to exceed that in the thoracic segment. 19It also follows that smooth muscle cells

are the major components ;n the abdominal section whereas supporting tissues like collagen and elastin are the main components of the thoracic aorta. A second difference between the thoracic and abdominal parts of the aorta relates to the ratio between collagen and elastin. The thoracic aorta contains more elastin and the abdominal aorta more collagen. 15

Results Histologic Features

Although the basic structure of the aortic media was as described in each case studied, there were wide variations in texture. Thus the configuration of the aorta varied considerably not only among the regions studied but also within each region studied, whether thoracic or abdominal. Changes were also observed in configuration with respect to age. Several features were outstanding. First, there was marked variation with regard to the amount of basophilic material, which ranged from small pools of mucopolysaccharides with minute "cysts" that did not interrupt the unit arrangement, to large pools with confluent cyst-like spaces that resulted in disruption of the lamellar build of the media. This feature has frequently been termed "cystic medial necrosis." Second, fragmentation of the elastin skeleton varied widely with respect to site and extent. These ranged from localized minimal elastin disruptions to large areas with marked fragmentation. This feature

cystic medial necrosis 23~

27

i .....

23 26

3O ..... 20

I II Ill FIGURE 1 (left). The three grades of cystic medial necrosis. A, B and C demonstrate the characteristics of Grades I, II and'Ill, respectively. In Grade I, minute "cysts" are present within a single lamellar unit; in Grade II the size and number have increased; in Grade ill large "cysts" extend over more than one lamellar unit. (Hematoxylin-eosin X500, reduced by 25 percent.)

FIGURE 2 (right). Pattern of distribution of cystic medial necrosis over the four aortic segments: 1 = ascending; 2 = arch; 3 = descending, at level of the diaphragm; 4 = abdominal.

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has been designated elastin fragmentation. A third feature, also variable, was the occurrence of fibrosis within the media. The presence of fibrosis was closely related to the presence of medionecrosis, a term def'ming the situation in which part of the media is devoid of nuclei. The particular characteristics of each of these features will be described in detail. CysUc Medial Necrosis

The "cysts" were observed in the presence of intact elastin lamellae and in the presence of fragmented elastin fibers. Three grades were defined as follows: Grade I: minute cysts were present within a single lameUar unit (Fig. 1A). Grade II: the size and number of cysts had increased, so that accumulation of cysts covered the total width of one lamellar unit (Fig. 1B). Grade III: the cysts were large and extended over more than one lamellar unit, either because of focal accumulations of small cysts with intact elastin lamellae or because of large cysts in an area with fragmented elastin fibers (Fig. 1C). Each case was classified according to the most severe degree of cystic medial necrosis found. It was observed in 61 of the 100 aortas and classified grade I in 23 specimens, grade II in 32 and grade III in 6. The findings in the five age groups, each containing 20 aortas, are shown in Table IA. The distribution over the various segments of the aorta is shown in Figure 2. Cystic medial necrosis of grades I and II was uniformly present throughout the total width of the media but was most prominent around the vasa vasorum in the outer part. A grade III change occurred most frequently in the middle part of the media. Cystic medial necrosis was found in 7 of the 10 aortas from children under 10 years of age; the youngest child with this finding was 1 1/2 years old.

ElasUn Fragmentation

This feature is defined as focal fragmentation of elastin lamellae in the aortic media. Three grades were recognized as follows: Grade I: fewer than five foci with elastin fragmentation in one microscopic field (magnification)<200), each focus comprising two to four neighboring elastin lamellae. The orientation of smooth muscle cells was preserved. Interruption of one elastin fiber alone was not interpreted as fragmentation (Fig. 3A). Grade II: five or more'foci with elastin fragmentation in one microscopic field (magnification ×200), each focus comprising two to four neighboring elastin lamellae. The foci could be confluent or scattered throughout the media (Fig. 3B). The orientation of smooth muscle cells was preserved. Grade III: presence of foci with elastin fragmentation in five or more neighboring elastin lamellae, irrespective of the number of foci per microscopic field. The smooth muscle cells of the media showed alterations in orientation (Fig. 3C). In studying elastin fragmentation as a histopathologic feature, the abdominal aorta posed a special problem. In most instances this part of the aorta showed transitions from an artery of the pure "elastin type" into one of the "muscular type." Concomitant with such tran-

TABLE I Incidence of Histologic Changes in the Five Age Groups With 20 Aortas Each Age (yr)

Grade I

Grade II

Grade Ill

Total

A. Cystic Medial Necrosis 0--20 20--40 40--60 60--80 80--100

4 3 6 6 4

9 7 8 6 2

2 3 0 1 0

15 13 14 13 6

0 1 1 3 3

15 20 20 20 20

0 0 1 3 5

1 13 17 20 20

0 0 3 6 4

4 6 14 20 20

B. Elastin Fragmentation 0--20 20--40 40--60 60--80 80--100

15 18 16 16 14

0 1 3 1 3 C. Fibrosis

0--20 20--40 40--60 60--80 80--100

1 8 5 6 4

0 6 11 11 11 D. Medionecrosis

0--20 20--40 40--60 60--80 80--100

3 4 3 7 4

1 2 8 7 12

sitions, splitting and fragmentation of elastin lamellae occur. It is therefore difficult to judge whether any fragmentation present is part of a natural or a disease process. For this reason the abdominal aorta was not included in the evaluation of the features of elastin fragmentation. Ninety-five of the 100 aortas studied exhibited elastin fragmentation, which was classified as grade I in 79, grade II in 8 and grade III in 8. There was no major difference between the aortas of male and female subjects. The occurrence of elastin fragmentation in the five age groups is shown in Table IB, and its distribution over the thoracic parts of the aorta is shown in Figure 4. The only aortas w i t h o u t elastin fragmentation were from children aged 6 years or less. The youngest patient with elastin fragmentation was 5 years old. Calculations based on observations in all sections evidencing elastin fragmentation revealed that grade I and II changes occurred in the luminal and middle layers in 97 and 95 percent, respectively, of cases but occurred in the outer third of the media in only 36 percent of cases. Only grade III fragmentation exhibited a diffuse distribution throughout the full thickness of the media. Fibrosis The histopathologic feature of fibrosis is defined as an increase in collagen. Three grades were recognized as follows.

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8_L elastin fragmentation

I

II

Ill

FIGURE 3 (left). The three grades of elastin fragmentation. A, B and C demonstrate grades I, il and Ill, respectively. In Grade I fewer than five foci of elastin fragmentation are present; in Grade II the number of foci has increased, but the foci are small and restricted to approximately two to four neighboring lamellae; in grade III the foci have extended beyond this number, and the cells show a disarray. (Elastic Van Gieson stain X200, reduced by 13 percent.) FIGURE 4 (right). Pattern of distribution of elastin fragmentation in the three segments of the thoracic aorta. The abdominal aorta was not included in the grading (see text).

37

fibrosis

35

31

".

.:,,~,..-.

~':.,~...,,.-~

29 26

~-,

~ :.._.,~.~. ~ . - . : - - - ~ - ~ . - ~ -

I II III FIGURE 5 (left). The three grades of fibrosis. A, B and C demonstrate grades I, II and III, respectively. Replacement of smooth muscle cells by collagen results in a dark area in the picture. (Van Gieson stain X45, reduced by 25 percent.) FIGURE 6 (right). Pattern of distribution of fibrosis over the four segments of the aorta.

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Grade I: an increase in collagen content in an area comprising less than one third of the total width of the media (Fig.

5A). Grade II: an increase in collagen in an area comprising between one and two thirds of the total width of the media (Fig. 5B). Grade III: an increase in collagen in an area comprising more than two thirds of the total width of the media (Fig.

5C). Fibrosis as thus defined was found in 71 of the 100 aortas. Grade I was present in 24 cases, grade II in 38 and grade III in 9. The presence of fibrosis within the five age groups is shown in Table IC, while its distribution over the four aortic segments is shown in Figure 6. Only one patient under age 20 years, a 19 year old youth, manifested fibrosis. Fibrosis was observed with greatest frequency in the inner two thirds of the media. Of all sections studied with this change, 95 percent exhibited fibrosis in the inner one third, 65 percent in the middle third and only 44 percent in the outer third of the media. Medionecrosis

Medionecrosis is defined as a focal loss of nuclei in the media. T h e overall decrease in the n u m b e r of nuclei was n o t assessed. T h e location a n d e x t e n t of areas of m e d i onecrosis strikingly r e s e m b l e d those o b s e r v e d with fibrosis. Medionecrosis was g r a d e d as follows: Grade I: focal loss of nuclei, in an area comprising less than one third of the total width (Fig. 7A).

AND BECKER

Grade II: focal loss of nuclei in an area comprising between one and two thirds of the medial thickness (Fig. 7B). Grade III: focal loss of nuclei in an area comprising more than two thirds of the total medial thickness {Fig. 7C).

Medionecrosis was present in 64 of the 100 aortas and was classified G r a d e I in 21 cases, grade I I in 30 and grade I I I in i3. T h e r e was no m a j o r difference between the aortas of m a l e and female. T h e presence of medionecrosis in the five age groups is shown in T a b l e ID, a n d its' distribution over the aortic s e g m e n t s is shown

T A B L E II Incidence of Changes in the Aortic Media in 20 Hypertensive Patients and 4 0 Age-Matched Normotensive Patients Total Medial Changes

Gradel

Cystic medial necrosis Hypertensive Normotensive Elastin fragmentation Hypertensive Normotensive Fibrosis Hypertensive Normotensive Medionecrosis Hypertensive Normotensive

Gradell Gradelll

no.

%

4 10

5 10

1 0

10 20

50 50

14 27

3 9

3 4

20 40

100 100

3 11

14 20

3 6

20 37

100 93

4 9

10 17

4 9

18 35

90 88

medionecrosis • "i

"

- •

"~

- -':

~"

-"..'-~'~_.~.-J-.

25 -- 20

® ,27

L _

_

_

I

II

Ill

FIGURE 7 (left). The three grades of medionecrosis. A, B and C represent grades I, II and III, respectively. Medionecrosis is recognized as an area devoid of nuclei. (Hematoxylin-eosin X40, reduced by 19 percent.) FIGURE 8 (right). Pattern of distribution of medionecrosis over the four segments of the aorta.

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in Figure 8. Only 4 of the 20 patients under age 20 years manifested medionecrosis. It was most frequently observed in the inner layer of the media. The luminal one third was affected in 94 percent of cases compared with 60 and 34 percent, respectively, for the middle and outer thirds.

Hypertension When the criteria of Hirst et al. 12 were applied retrospectively to the patients studied, 22 of the 100 were judged to have hypertension during their lifetime. Twenty of these 22 patients were over 40 years of age. The five histopathologic features studied in these 20 patients were compared with those in the remaining 40 patients in the group over age 40 years (Table II). No major differences were noted between the two groups. The medial thickness of the ascending aorta was measured from the histologic sections in the 20 patients with hypertension and the 40 normotensive patients. The hypertensive patients had a medial thickness of 2.06 + 0.15 mm (mean ± standard deviation). The normotensive patients had a mean thickness of 1.92 + 0.30 mm. This difference was not significant.

Discussion The pathogenesis of dissecting aneurysm of the aorta has often been related to intrinsic disease of the media. Several histopathologic features, such as medionecrosis, 4-7 cystic medial necrosis 3,s-1° and elastin fragmentation, 7,H have been considered specific for such disease. However, our study has demonstrated that each

of these histopathologic features can occur in an apparently normal aorta (Fig.9). W e therefore believe that the described medial changes in the aortas of patients with dissection are not specifically causative for this disease process. Cystic medial necrosis: In this study we have adopted the definition and grading system of cystic medial fibrosis used by Edwards et al.3,1°Other definitions of this term exist.Erdheim, 9 who introduced the phrase, meant itto describe the combination of (1) necrosis of the smooth muscle cells,in accord with Gselrs description of medionecrosis (see later),and (2) a mucold degeneration of the media. Erdheim believed that a pathologic accumulation of ground substance caused the media to degenerate although he offered no explanation for the occurrence of this medionecrosis. Since Erdheim's studies the term cystic medial necrosis has gained wide recognition but is commonly used to describe only the feature of mucoid degeneration of the media. Thus, the presence of basophilia and pools of mucopolysaccharides is often interpreted as a manifestation of a degenerative disease although Erdheim had previously pointed out that basophil/a is also found in normal aortic media. Today, the diagnosis of cystic medial necrosis is generally made solely on the basis of the presence of cysts within basophilic substances. Thus, in m a n y instances, a normal situation is interpreted as a pathologic change, an interpretation that is then in complete accord with the c o m m o n view of the pathogenesis of the dissection.Our findings also support

100 control aortas number

grade

I rrr

OJ

o

40--60

0 -20

0 - 20

P_0-40

60--60

U

60-100

yr

yr

40--60

60--80

80-100

40-60

60-B0

60-100

cystic medial necrosis

elastin f r a g m e n t a t i o n

10

0

0 - PO

20-40

yr

o s

10

0

18

~0 -- ] 2 0

~ -~ 20-40

~ 40-60

60-60

aO-lO0

y r

medionecrosis

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FIGURE 9. Results in 100 normal aortas classified into five age groups with 20 aortas each. The prevalenceof the three grades of the four histopathologic features is demonstrated for each group.

NORMAL AGING AORTA--SCHLATMANN AND BECKER

Erdheim's belief that the cysts are artificial, occurring as a result of shrinkage during histologic procedures. Our study and that of Erdheim indicate that cystic medial necrosis is probably an expression of metabolic activity rather than the result of a degenerative process. Evidence to support this hypothesis is adduced from the observation that cystic medial necrosis exhibits a reciprocal correlation with other histopathologic features such as fibrosis and medionecrosis (see later). Elastin fragmentation: The hypothesis of fragmentation of the elastin skeleton of the aortic media as a primary process underlying dissection has been emphasized by Gore et al. 7,11 They consider it an expression of a congenital disturbance of the connective tissues and found it particularly prominent in patients with a dissecting aneurysm who were under age 40 years. Other investigators have interpreted elastin fragmentation as secondary either to smooth muscle cell necrosis 4,2° or to a pathologic accumulation of ground substance. 9,1° Our study of normal aortas demonstrated elastin fragmentation in almost every case, its severity increasing with age. We also demonstrated that elastin fragmentation is more pronounced in the ascending aorta and the aortic arch than in the descending thoracic aorta, whereas the inner layers of the media are those most severely affected. Areas with fragmented elastin fibers also exhibited concomitant changes such as an increase in acid mucopolysaccharides and reparative changes such as a proliferation of smooth muscle cells and the formation of connective tissue fibers. We suggest therefore that, when viewed in toto, "elastin fragmentation" is a histopathologic expression of a traumatized media. Moreover, by virtue of its preponderance within the inner layers of the media, we contend that the damaging effects are initiated by forces within the aortic lumen and that hemodynamic impact is the initiating cause of this histopathologic feature. Fibrosis: Our study has confirmed the generally accepted view that the aorta exhibits increased collagen with age. 11,21-23However, our study has also shown that fibrosis mainly occurs within the inner layers of the media and that its location within the media is closely correlated with that of medionecrosis (see later). The ascending aorta and aortic arch are the segments most severely affected. This is again suggestive that fibrosis is a response to long-standing trauma to the media, and as such this feature can be interpreted as an end stage of a reparative process. Medionecrosis: The possible significance of medionecrosis in the pathogenesis of a ruptured aorta was first noted by Gsell. 4 He described focal areas in the aortic media with loss of nuclei and suggested that medionecrosis could be caused by a variety of infectious diseases and intoxications. Subsequent investigators supported the concept that medionecrosis is the prime mechanism underlying aortic dissection. 2°,24-27 Gore et al. 5-7 also considered medionecrosis the primary underlying pathogenetic mechanism in patients over 40 years of age, whereas they implicated elastin fragmentation in younger patients. 7,11 Indeed, Gore and Seiwert's muscular type 6 of medial degeneration de-

scribes the feature of medionecrosis. They related its occurrence to stress exerted on the aortic media, which they believed also explained their observations that the same aortic features could be found in older persons and in hypertensive patients. The difference from the aorta with dissection is quantitative rather than qualitative. Previous investigators 1,2,24 have pointed out that medionecrosis may be present in a normal aging aorta. Our study confirms this view. It also shows that medionecrosis is closely related, both in frequency and in site of occurrence, to fibrosis, a relation previously observed by Weise I although he did not comment on its significance. The term medionecrosis seems to us a misnomer because conclusive evidence for the presence of tissue necrosis has never been brought forward. We suggest that in the area involved, the smooth muscle cells have been replaced by collagen, thereby accounting for the transition from an area rich in nuclei into an area with apparent loss of nuclei. Such transitions are well documented in other pathologic states, of which aging granulation tissue is an excellent example. 2s We therefore tentatively speculate that medionecrosis represents an adaptation to stress. Hypertension: The 22 subjects in our study with hypertension according to the criteria of Hirst et al. 12 showed no major differences with respect to aortic medial features when compared with 40 age-matched normotensive subjects. This result may appear surprising because hypertension is generally believed to provoke medial changes. However, careful review of previous studies enables this premise to be questioned. Although Rottino 2 stated that medionecrosis increased in frequency and degree in patients with hypertension, he compared his findings in hypertensive patients with those in all normotensive subjects studied. When his findings in the hypertensive patients are compared with findings in age-matched normotensive subjects, the differences between the two groups are less striking. Indeed, recalculation reveals that medionecrosis was present in 51 percent of his hypertensive patients and in 49 percent of his normotensive patients; this difference is no longer significant. A similar situation is encountered in the studies of Carlson et al.,3 who claimed that the aorta of patients with hypertension had an increase in cystic medial necrosis over norinal. However, in their calculations they omitted two hypertensive patients, each under 20 years of age. When these two patients are included, recalculation reveals that the aorta of normotensive subjects showed more evidence of cystic medial necrosis than that of hypertensive patients. It is of interest that in a subsequent study from the same center 29 a correlation between hypertension and cystic medial necrosis could no longer be found. Our study did not attempt to investigate the role of hypertension in provoking the medial changes. Indeed, the widely accepted criteria of Hirst et al. 12 for hypertension were applied in retrospect. This may have influenced our findings, which do not necessarily contradict the view that in long-standing, severe hypertension medial changes are provoked. Our study does

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show, however, that in a randomized study of aortas, some of them undoubtedly from patients with hypertension, the aforementioned medial changes are not increased. In accord with previous studies,3°,3zwe did find hypertrophy of smooth muscle cells.

Conclusions Several important conclusions can be drawn from our investigations. First, it appears that histopathologic features thought to be specific medial defects underlying aortic dissection are also observed in the normal aorta. We therefore question the claimed specificity of these structural features, particularly when presented as specific independent abnormalities. Second, all of these features show a striking correlation with aging, so that one may argue that the changes observed represent

the normal aging process for the aorta. Third, the histopathologic findings show a strikingly close relation in onset and location within the media. There ispreference for the thoracic segments of the aorta and for the inner layers of the media. These findings suggest to us that the features actually represent the morphologic expression of an interaction within the aortic wall of processes of injury and repair. Hemodynamic impact is, in our opinion, the initiating cause of these processes.

Acknowledgment We gratefully acknowledge the cooperation of Dr. J. Zeldenrust of the Gerechtelijk Geneeskundig Laboratorium, The Hague. Technical assistance was given by Miss H. J. Dijk, Mr. E. M. E. Heeren and Mr. M. J. Klaver. We thank Miss M. I. Schenker for her assistance with preparation of the manu-. script.

References 1. Welse W: Medianekrosen, eine Untersuchung am laufende Sektionmaterial. Beitr Pathol Anat AIg Pathol 93:238-278, 1934 2. Rottlno A: Medial degeneration of the aorta. A study of two hundred and ten routine autopsy specimens by a serial block method. Arch Pathol 28:377-385, 1939 3. Carlson RG, LIIlehel CW, Edwards JE: Cystic medial necrosis of the ascending aorta in relation to age and hypertension. Am J Cardiol 25:411-415, 1970 4. Gsell O: Wandnekrosen der Aorta ais selbstandige Erkrankung und ihre Beziehung zur Spontanruptur. Virchows Arch Pathol Anat 270:1-36, 1928 5. Gore h Pathogenesis of dissecting aneurysm of the aorta. Arch Pathol 53:142-153, 1952 6. Gore I, Selwert VJ: Dissecting aneurysm of the aorta: pathologic aspects and analysis of eighty-five fatal cases. Arch Pathol 53: 121-141, 1952 7. Gore I, Hlrst AE Jr: Dissecting aneurysm of the aorta. Clinicalpathologic correlations. Cardiovasc Clin 2:239-260, 1973 8. Erdhelm J: Medionecrosis aortae idiopathica. Virchows Arch Pathol Anat 273:454-479, 1929 9. Erdhelm J: Medionecrosis aortae idiopathica cystica. Virchows Arch Pathol Anat 276:187-229, 1930 10. Edwards JE: An Atlas of Acquired Diseases of the Heart and Great Vessels, Vol III. Philadelphia, W B Saunders, 1961, p 10671120 11. Gore h Dissecting aneurysm of the aorta in persons under forty years of age. Arch Pathol 55:1-3, 1953 12. Hlrst AE, Johns VJ, Klme SW: Dissecting aneurysm of the aorta: a review of 505 cases. Medicine 37:217-279, 1958 13. WHO Technical Report Series no. 143: Classification of Atherosclerotic Lesions. Geneva, 1958 14. Wollnsky H, Glagov S: Structural basis for the static mechanical properties of the aortic media. Circ Res 14:400-413, 1964 15. Wollnsky H, Glagov S: A lamellar unit of aortic medial structure and function in mammals. Circ Res 20:99-111, 1967 16. Milch RAM: Matrix properties of the aging arterial wall. Monogr

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Surg Sci 2:261-341, 1965 17. Berry CL: Growth, development, and healing of large arteries. Ann Coil Surg Engl 53:246-257, 1973 18. WollMky H- Comparison of medial growth of human thoracic and abdominal aortas. Circ Res 27:531-538, 1970 19. Dustan HP: Atherosclerosls complicating chronic hypertension. Circulation 50:871-879, 1974 20. Shennan T: Dissecting Aneurysms. Special Report, Medical Research Council, London, His Majesty's Stationary Office, 1934 21. Wellman WE, Edwards JE: Thickness of the media of the thoracic aorta in relation to age. Arch Pathol 50:183-188, 1950 22. Suck RC: Histogenesis and morphology of arterial tissue. In, Atherosclerosis and its Origin (Sandier M, Boume GH, ed). New York, Academic Press, 1963, p 1-38 23. Bertelsen S: The role of ground substance, collagen and elastin fibers in the genesis of atherosclerosis. In Ref 22, p 119-165 24. Celllna M: Medionecrosis disseminata aortae. Virchows Arch Pathol Anat 280:65-86, 1931 25. Rottlno A: Medial degeneration in a nonruptured aorta appearing syphylitic macroscopically. Arch Pathol 27:320-327, 1939 26. Rottlno A: Medial degeneration of the aorta as seen in twelve cases of dissecting aneurysm. Arch Pathol 28:1-10, 1939 27. Rottlno A: Medial degeneration, cystic variety in unruptured aortas. Am Heart J 19:330-337, 1940 28. Gabblanl G, Ryan GB, Malno G: Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia 27:549-550, 1971 29. Murray CA, Edwards JE: Spontaneous laceration of ascending aorta. Circulation 47:848-858, 1973 30. Knlerlom HJ, Hueber R: Quantitative morphologische Untersuchungen an der Aorta des Menschen. Beitr Pathol Anat 140: 280-297, 1970 31. Wollnsky H: Long-term effects of hypertension on the rat aortic wall and their relation to concurrent aging changes. Circ Res 30: 301-309, 1972

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