The pathogenesis of arteriosclerosis

The Amerkan

Journal

of Cardiology NUMBER 3

MARCH 1958

VOLUME I

Edi tori al The Pathogenesis of Arteriosclerosis

N

is valid without

o DISCUSSION

a definition.

is now particularly sclerosis

and

are

one can exist without

atherosclerosis tative

arterio-

more

arbitrary

sharply

speaking

it defines

studies the maturation become

manifest,

present

in such

all

enough.

Other

increase

in

applies

animals

as our

lesions

who

own

have

and

are

live

omnipresent,

and

extent

these

as abnormal

normal

involuntary

undergo

with

181

70 yr

190

from

birth

two

age.

to old age.

In

layer.

A

distinct

involves

internal

elastica

also

The

the

may

the artery

has been

term

applied

of the intima

absent

after of

in the course

“hyperplastic”

morphogenesis.

to this

arterio-

normal

in-

If, therefore,

hy-

and of the elastica

may

earliest lesions, then

is not always an aging phenom-

as currently

Fortunately

arteries

vessels thickening

is of the elastic or muscular

are never

The

arteriosclerosis enon

small

progressive

and of the elastica differ in intensity

volutionary

clinical

viewed

but begins

and anatomic

at birth.

arteriosclero-

sis are not always coexistent.

contrast

This biologic interpretation of arteriosclerosis have explains the difficulty some observers had in determining when physiologic aging ends

their birth

but continue to grow as the years progress. The endoAt birth there is hardly any intima. thelium lies directly upon the elastica which is single

of the

be viewed as the inescapable

lesions that

life. 5

sclerosis

but as part of the

changes

and

middle

perplasia

to other organs the arteries do not attain maximum histologic differentiation at

MARCH,1958

124

50 yr

of growth.

as well to the lower animals.2J

not be viewed

a

35 yr

type but they

ARTERIAL CHANGES WITH AGE Being

54

arteries

whether

long

things being equal these lesions

intensity

6

10 yr

the intima

a vascular

who

Intima (p)

Reduplication

of the and

ages:

begins as early as the second year in the larger

thickening

a reduplication

are universal

to

changes

first a collagenous

shows the measure-

Age

if one

from birth

Histology4

Birth

is no Biolog-

since

of arteries

and later

These

system

itself;

years two morphological

of the intima elastica.

There

need to define arteriosclerosis.

the senescent

only

Schafer’s

the other and that

of arteriosclerosis.

already becomes visible at the The following data taken

ments of the intima at different

when it does occur is but a facul-

lesion

ically

because

atherosclerosis

from

I1 have tried to show that morphologi-

defined. cally

pertinent

of intima

end of the first year.

This

of an artery was labeled “arteriosclerosis.”

This

layer

The time is long past when any hardening

and disease begins. For instance, BrenneP reports an incidence of 80 per cent arteriosclerosis of the pulmonary artery, his criterion

collagenous 295

Editorial being the thickening servations occur

of the intima.

the only normal

in children.

perfectly calculated artery

the

This

is is

vessels;

to the gross or naked eye in the pulmonary

is determined

intima,

cent.

when

of arteriosclerosis

which

in the

but

according

appearance

Brenner incidence

Anatomically,

correct,

by lipoid

the incidence

latter

In his obarteries

instance, on the posterior wall of the thoracic and abdominal aorta; at the site of vascular fixation, such as at the origin of the intercostal

pulmonary

is only

observation

has a deep significance

deposits

the rigid

six

directly

as we shall

per see

in respect to pathogenesis.

of the

elastica

pensatory many

hyperplasia

may

phenomena

evidences

that

these

prolonged

lesions

been cited

are

gross

arteriosclerosis

circulations. that

the

artery

pressure

arteriosclerosis

is certainly

very

of the pulmonary deposits

Sudan

stains

grossly (2)

When

unless

circulation

the

frequency cardiac

hepatic

and

congestive

production

pulmonary

failure;

of the

by

already

except

age

of arteriosclerosis

is

disorders,

those

in degree.

mitral

of

the

hypertensive

disease

It has speaking, disease

in normotensive Because of the and congenital

arteriosclerosis

in

in the

of the intima,

of the

pul-

pressure

may

rarely

veins

say

that

occurs

prolonged in the

sa-

aneuryism.

hyperplasia

In

of

the

in veins even when

the

thickened.

These

impressive

lesions for our

even with the most aggravated

prolonged

proaches

be

cava,

and in the venous

in the veins are particularly and

in

circulation;

arteriovenous

is profoundly

thesis because

can

in the vena

in the portal vein in hyper-

portal

of an I

elastica intima

arteries

a hyperkinesis

morphologically in

venous

artery

were

pressure

for instance,

passing

is superimposed,

lesions

of

prolonged

segment

not be demonstrated

in no way from

individuals

a

demonstrated,

aorta.

can be predicated.

hypertension,

the

The

exemplified

veins is close to zero, thickening

venous

in constrictive

that,

arterial

Since

showed

intima.

is negatively

the

a hypertension

they

phlebosclerosis.

thickened

pulmonary

of pulmonary

when

of pressure

ends of an artery

phenous veins in varicosities;

and the lesions are intensified.

shown

differ

could except

function,

for

lowered been

in

a markedly

tension

visible.

a normal limit

the

that

the divided

time

where

the

or lesser

of the pulmonary

rare,

In a study of hundreds lipoid

in

one-sixth

between in

to

between

greater

observation is especially He showed that a vein interposed

even in senility, never occurs except in instances

These are :

in incidence

Carrel’s’l

showed

is due to the circumstance

normal

is only

Gross

the

pressure.

of the

This

that

compensatory

arterial

The independence

(1)

as com-

and in previous studies7s8

have

normal

viewed

septum.

effect

in those

artery that lie against

bronchus; and in the endocardium opposite a perforation of the ventricular

pertinent.

of the intima and

be justly

of the wall of vessels

sections of the pulmonary

ARTERIAL CHANGES AND PRESSURES The progressive

in the portions

of the dura that lie next to the bone;

pressure,

pericardium,

for instance,

it never

the normal systemic arterial

even appressure.

The testimony adduced affords decisive evidence in my opinion, that the prolongation of the normal conditioning earliest words,

intraarterial factor

lesions

of

production

of the

arteriosclerosis.

we maintain

sufficiently

pressure is the main

in the that

continued

In other a normal function

can

ultimately

cause

vascular disease sufficient at times to compromise life.

I have suggested

therefore

the following

monary artery is common in the juvenile and even in the infantile years. (3) Arteriosclerosis is appreciably less in

equation :

hypotensive individuals.‘O It is notoriously less in patients with active tuberculosis, age for

Apparently, Thoma’s12 third law of the growth of vessels, namely, that the thickness of a vessel

age. (4)

arteriosclerosis

is dependent The

effect

of

intravascular

arterial pressure is well exemplified in the intensification of the lesions at points where the pressure is exerted

against

an

external

resistance,

for

= intravascular

on the difference

vascular and extravascular app,lied to the embryonal

pressure

between

X time

intra-

pressure, which he development of ar-

teries, is perfectly applicable to postembryonal growth. The important conclusion from the THE

AMERICAN

JOURNAL

OF

CARDIOLOGY

Editorial premises

we

have

submitted

sclerosis of the greater

circulation

by hyperplasia

of the

not

because

reversible

pressure

cannot

mising

is that

as manifested

intima

and

normal

be abolished

arterio-

elastica

is

intravascular

without

compro-

those

occurring

there

were

impressive

striking

being

to the

arterial

produced

the

Teleologically,

pressure

may

hyperplasia

viewed as an adaptation

to the progressive that

normally

be

rise of

proceeds

in human

by

differences,

tree

and

the

have

noteworthy

differences

been

then

most it was

and

then

some of these

overcome,1g~20 but first,

remain:

that in experimental

two

the cir-

atherosclerosis

from birth to old age, or if there is no perceptible

there

increase,

level of the cholesterol

(this is largely dependent

on species difference)

; and second, that human

normal

to the prolonged pressure.

will be worn will

take

heavier

maintenance

In other words,

out by vehicles,

longer

with

of the

a pavement

but the process

lighter

vehicles

than

atherosclerosis

hyperplasia

of the intima

except

and

elastica

been

made

chemical

sis;

tion of the plasma

circulation.

especially

However,

of arteriosclerosis imposed,

pulmonary

in the further

other

generally

in the

lesions

classified

substance

saccharides

consisting

in the

walls

deposit

is already

creases

with age.‘b-17

be

hyaline,

only

one

Of

worth

a

phase

years The

of

these

later

serious

lipoid deposition,

vessel.

This and in-

in children14

In addition, there may calcareous, and lipoid

mucoid,

degeneration.

of a meta-

of mucopoly-

of the

visible

changes,

consideration

vascular

importance

disease

that

in

a vast amount

of atherosclerosis

not only because

looms

it is the deposition arteriosclerosis it largely

to the narrowing

of the lumen. lends

itself

to

reproduction

and its elimination

has aroused

hopes

that

to the rising

visible

contributes

or prevention especially of coronary

his

the

lipoproteins

upon

plasma

co-workerszl

studied the distribution

the ratio

have

in

of the alpha

in the plasma

of

phospholipid. addition and beta

in different

animals,

in infants, young men and women and in human conditions

associated

with atherosclerosis.

Gof-

man’s studiesz2 of the lipids with the ultracentrifuge are familiar.

Both Barr’s and Gofman’s

studies, while suggestive, namely, mate

have the same defect,

that their findings bear only an approxi-

but

cidence

not a consistent

relation

to the in-

of atherosclerosis.

Thus

far

measuring

no

method

has

been

devised

of

the lipids in the blood quantitatively

or qualitatively

by physical or chemical

methods

which afford any ability to predict the incidence

feeding to rabbits.

The

tion only one factor,

problem

important

that enters into the production sis, Most

is no doubt that the deposits of lipid mim1958

and

depends

to

it has

of athero-

difficult because such studies take into considera-

The experimental study of atherosclerosis was begun by Anitschkow and Chalatow18 nearly

MARCH,

Barr

for instance,

the development

sometimes

cholesterol

by

in the composi-

of atherosclerosis.

EXPERIMENTAL ATHEROSCLEROSIS

There

the

have

discrepancies

experimental

disease, may be controlled.

forty years ago by cholesterol

sclerosis

lipids;

ob-

hyper-

Furthermore,

its ravages, incidence

large

of lipid

in the intima that renders but also because

recent

of study.

grossly,

in respect

the is the

in other words, atherosclerosis,

has stimulated

atherosclerosis

super-

as degenerations.

I refer to fibrosis and the deposition chromatic

evolution

become

that

syn-

biliary

of attempts

these

or physical differences

been shown

by a hypernephrotic

or familial

A number

to explain

may be the only lasting lesions of arteriosclerothis applies

to the blood

prolonged

in essential

cholesterolemia.

and

in the

hypothyroidism,

struction,

ARTERIAL DEGENERATION

relationship

is unaccompanied

cholesterolemia drome,

ones.

The

was no linear

that

means

Since

but

distribution

the fact

unphysiologic

differences cumstance

beings,

the lack of selective

only in herbivora.

life itself.

intraarterial

icked

namely

the

observers

always contains

lipid

content

fail to consider a certain

quota

is rendered as it may be,

of atheroscleroof the

blood.

that the blood of cholesterol

and other lipids. It is not a question of either/ or but only of more or less. In other words, in respect to the blood cholesterol the most we can hope for is a partial but not a complete solution

of the problem.

Editorial FACTORS IN ATHEROSCLEROSIS Other

factors

atherosclerosis, (1)

enter

atherosclerosis

in hypertensive

and accounts observed

atherosclerosis

is practically hypertension

of

for the

cholesterolemia

and a normal

blood

than with a hypercholesterolemia

and

it will take

a lesser time

with prolonged atherosclero-

lived animals,

hepatic,

blood

is induced.

of the effect of is a negative is exceedingly

In examining

phlebosclerosis.24

pulmonary

the vena cava, I have seen atheroma

hun-

ously long lived. experimental greater

Certainly

circulation,

in phlebo-

atherosclerosis

of atherosclerosis

the vascular

The evidence from

the

First,

there is a striking

observers

scurvy,2x and syphilis.

act as precursors In

sectioning

to the deposition many

found lipoid deposition panied by a hyperplasia contends secondary but

the

Many

believe that the mucopolysaccharides

that

the

arteries

I have

that

in the pulmonary

the

never

initial

are

reverse

relationships

artery is a valid argument

and

deposit

tensive

states

that

in the

Moon athero-

of the intima

preceded

the deposition

Also, they showed that the induction

of experimental atherosclerosis bore little resemblance to the histogenesis of human coronary atherosclerosis. (3) Finally, the Dynamic Factor of Time: The neglect of this factor explains why all attempts to ,formulate linear relationships between experimental factors and atherosclerosis have thus far failed. Anitschkow recognized the time element years ago when he showed that atherosclerosis can be produced with a

the

blue.

lipid

wall.

the

atherosclerosis Third,

of the

amount

in the

there

of lipid in hypergreater

is

or

of

in hypo-

less.

areas

that

revealed

Fourth,

the

dyes such

Fifth, in hypercholesterolemia convincing

showed

in

Second,

Conversely,

to colloidal

its are greater Most

of the

showed that the lipid was deposited

same

permeability

reasons:

in chemistry

is in the intima. whether

imbibition

following

similarity

human

circulations.

Anitschkow

the

in the amount

states,

lesser

exist

sclerosis that thickening

that followed

the

for

in the arterial

tensive

Wilens2g

thickenings

of

unless the time

by direct

distribution

and

of the intima. intimal

of lipid.

in

is an increase

the same sequence occurs in all arteries. and Rinehart30 demonstrated in coronary

the fibrous plaques

and

plasma

arises

plasma,

in the intima unaccom-

and the results of the lipid deposition; fact

atherosclerosis

experimental

of lipid.

inci-

sections

is strong that most of the lipid

tion of lipid in the vessel wall; cauterization,26J7

on the

in different

injury of the vessel wall predisposes to the deposidetergents,25

is a senescent

studies

tree are valueless

hy-

of the

factor is considered.

that

this includes in-

in pulmonary hypertension

Statistical

in

adrenalin,r8

in every field except

and in juvenile

dence

testimony

of arteriosclerosis2f3

is in birds who are notori-

atherosclerosis,

phenomenon.

of

the longest

at least in terms of their captivity,

The greatest incidence

pertension

explains

in the incidence

since by and large,

show the highest incidence

veins, and

sclerosis, but very rarely. (2) The Changes in the Vessel Wall Previously is abundant

some of the species difference arteriosclerosis

hypertension evidence

The time factor

circulation.

even with a normal

by

an athero-

or a hypercholes-

that atherosclerosis

produced

to cause

probably

one, namely,

jury

it

with

terolemia.

upon atherosclerosis

There

a normal pressure

other

atherosclerosis

sclerosis with a hypertension

A highly confirmatory

Described:

words,

In

years.

hypertension in

prolonged.

is

artery

pulmonary

provided

dreds of portal,

periment

in the juvenile

Faber23 showed that experimental

rare

if the ex-

of the pulmonary

the

sis can be produced

states

largely

always associated

cholesterol

of

The fact that atherosclero-

pronounced

is acknowledged, Gross

the production

of hypercholesterolemia

will take longer to produce

Hypertension:

sis is more

into

viz. :

lesser degree

than

greatest

as trypan the depos-

in normocholesterolemia.

is the work of Wilens31 who

experimentally

that

with

sufficient

into the pressure, lipid could be expressed wall of vessels. Inasmuch as the plasma lipid exists in a colloidal form and in the artery as a granular deposit, the presumption is that the intima takes part in this transformation. Not all the lipid enters the vessel wall by imbibition. Winternitz and his co-workers have adduced convincing evidence that some lipid is the result of hemorrhage from the rupture of the intimal capillaries. THE

AMERICAN

JOURNAL

OF

CARDIOLOGY

Editorial There is no doubt that experimental atherosclerosis is reversible, that is, the lipid disappears if the experiment is stopped at a proper time, even though connective tissue changes persist in the wall of the artery. But there is strong doubt whether human atherosclerosis is rebecause the most versible, even partially, important elements that enter into its production, namely normocholesterolemia, intravascular pressure, the changes in the ground substance and the time factor cannot be eliminated. The most that can be hoped for is a cessation or a slowing of the process. The only conditions in which human atherosclerosis may be reversible is in the hypercholesterolemic states previously mentioned. It is obvious that owing to the numerous interacting factors that enter into the production of arteriosclerosis, a complete reversal or a prevention will be an unattainable project. That is why arteriosclerosis has always been with us, in antiquity,32 and all climes, in all races. It is an inescapable destiny. ELI MOSCHCOWITZ New York, New York RErzr~zNo~s

4. 5. 6. 7. 8. 9. 10. 11. 12.

13.

MOSCHCO~~TZ, E. : Hyperplastic arteriosclerosis versus atherosclerosis. J.A.M.A. 413: 862, 1950. Fox, H., in COWDRY, E. V.: Arteriosclerosis. Macmillan, New York, 1933. CRONIN,M. T. T. and RATCLIFFE, H. L. : Arteriosclerosis in captive wild mammals and birds. Am. J. Path. 33: %b, 1951. SCHAFER, E. A. S. : Text Book of Histology. Lea & Febiger, Philadelphia, 1920. BELL, E. C., in COWDRY, E. V.: Arteriosclerosis. Macmillan, New York, 1933. BRENNER,0. : Pathology of the vessels of the pulmonary circulation. Arch. Znt. Med. 56 : 21 I, 1935. MOSCHCO~ITZ, E. : Hypertension of the pulmonary circulation. Am. J. M. SC. 174: 388,1927. MOSCHCO~ITZ, E. : Vascular Sclerosis. Oxford, New York, 1942. MOSCHCO~ITZ, E. : Unpublished data. HUNTER, A.: Blood pressure among standard lives. J. Actuar. Statistics 70: 60, 1939. CARREL, A. : Technique and remote results of vascular anastomosis. Surg. Gyaec. d Obstct. 1: 1, 1912. THOMA, R.: Ueber die Stromung des Blutes in der Gcfassbahn und die Spannung der Gefssswand. Beitr. z. path. Anat. u. z. allg. Path. 67 : 92, 19191920. LEARY, T.: The genesis of arteriosclerosis. Arch. Path. 32: 507, 1941.

MARCH, 1958

299

14. TAYLOR, H. E.. The role of the mucopolysaccharides in the pathogenesis of intimal fibrosis and atherosclerosis of the human aorta. Am. J. Path. 29: 87, 1953. Ueber Mukoides Bindegewebe 15. BJORLINC, E. : Virch. Arch. f. path. Anat. 205: 71, 1911. The human aorta sulfate-containing 16. FABER, M.: polyurinides and the deposition of cholesterol. Arch. Path, 48: 312, 1949. 17. SSOLOWJEW,A. : Ueber das Verhalten des Zwisschensubstanz der Aortenwand bei Atherosklerosie. Virch. Arch. f. path. Anat. 250 : 339, 1924. Ueber ex18. ANITSCHKOW,N. and CHALATOW, S.: perimentelle Cholestrin steatose und ihre Bedeutung fiir die Enstehung einziger pathologische Processe. Cent. f. allg. Path. n. path. Anat. 24: 1, 1913. Experimental Athero19. KATZ, L. N. and STAMLER, J.: sclerosis. Thomas, Springfield, Ill., 1953. 20. STEINER, A. and KENDALL, F. E.: Atherosclerosis and arteriosclerosis in dogs following ingestion of cholesterol and thiuracil. Arch. Path. 42: 433, 1946. Pro21. BARR, D. P., Russ, E. M., and EDER, H. A.: tein-lipid relationship in human plasma in atherosclerosis and related conditions. Am. J. Med. 11 : 480, 1951. 22. JONES, H. B., GOFMAN, J. W., LINDGREN, F. T., LYON, T. P., GRAHAM, D. M., STRISOWER, B., and NICHOLS,A. V.: Lipoproteins in atherosclerosis. Am. J. Med. 11: 358,195l. 23. FABER, M.: The cholesterol content of the human aorta in relation to serum cholesterol concentration. Act. med. Scandiaav. 125: 419, 1946. 24. GEIRINGER,E. : Venous atheroma. Arch. Path. 48: 410, 1949. 25. DE SUTO-NAGY, G. I. and WATERS, L. L.: The effect of altered lipid metabolism on experimental lesions of the coronary arteries. Circulation 4: 468, 1951. 26. SCHLICHTER,J. G., KATZ, L. N., and MEYER, J.: The occurrence of atheromatous lesions after cauterization of the aorta followed by cholesterol feeding. Am. J. M. SC. 218 : 60, 1949. 27. SSOLOWJEW, A.: Expcrimentelle Untersuchungen iiber die Bedeutung von lokaler Schldigung fiir die Lipoidablagerung in der Arterienwand. Ztschr. f. d. ges. cxper. Med. 69: 94, 1930. 28. WILLIS, G. C.: Experimental study of intimal in atherosclerosis. ground substance Canad. M. A. J. 69: 17, 1957. 29. WILENS, S. L. : The nature of diffuse intimal thickening. Am. J. Path. 27: 825, 1951. 30. MOON, H. D. and RINEHART, J. F.: Histogenesia of coronary arteriosclerosis. Circulation 6 : 481, 1952. 31. WILENS, s. L.: The experimental production of lipid deposition in excised arteries. Sn’encc 114: 389, 1951. 32. RUFFIER, A. M.: Studies in the Paleopatholo,gy of Bgypt. Univ. Chicago Press, Chicago, 1922.