PATHOLOGY
The whole subject of the pathology of arteriosclerosis has been much
enriched by the study of the experimental lesions produced by various
drugs and microorganisms upon the aortas of rabbits. Simple atheroma
must not be confused with the lesions of arteriosclerosis. The small
whitish or yellowish plaques so frequently seen on the aorta and its
main branches, may occur at any age, and have seemingly no great
significance. Such plaques may grow to the size of a dime or larger, and
even become eroded. They represent fatty degeneration of the intima
which, at times, has no demonstrable cause; at times follows in the
course of various diseases, and undoubtedly is due to disturbances of
nutrition in the intima. Except for the remote danger of clot formation
on the uneven or eroded spot, these places are of no special
significance, and are not to be confused with the atheroma of nodular
sclerosis.
The lesions of arteriosclerosis are of a different character. It has
been customary to differentiate three types: (1) nodular; (2) diffuse;
(3) senile. It must be understood that this is not a classification of
distinct types. As a rule in advanced arteriosclerosis, lesions
representing all types and all grades are found. The nodular type,
however, may occur in the aorta alone, the branches remaining free. This
is most often found in syphilitic sclerosis where the lesion is confined
to the ascending portion of the arch of the aorta.
The retrogressive changes of advancing years can not be rightly termed
disease, yet it becomes necessary to regard them as such, for the senile
changes, as we shall see, may be but the advanced stages of true
arteriosclerosis. Much depends on the nature of the arterial tissue and
much on the factors at work tending to injure the tissue. A man of
forty years may therefore have the calcified, pipe stem arteries of a
man of eighty. Our parents determine, to great extent, the kind of
tissue with which we start life. The arteries are elastic tubes capable
of much stretching and abuse. In the aorta and large branches there is
much elastic tissue and relatively little muscle. When the vessels have
reached the organs, they are found to be structurally changed in that
there is in them a relatively small amount of elastic tissue but a great
deal of smooth muscle. This is a provision of nature to increase or
decrease the supply of blood at any point or points.
The aorta and the large branches are distributing tubes only. It is
after all in the arterioles and smaller arteries that the lesions of
arteriosclerosis do the most damage. A point to be emphasized is that
the whole arterial system is rarely, if ever, attacked uniformly. That
is, there may be a marked degree of sclerosis in the aorta and coronary
arteries with very little, if any, change in the radials. On the
contrary, a few peripheral arteries only may be the seat of disease. A
case in point was seen at autopsy in which the aorta in its entirety and
all the large peripheral branches were absolutely smooth. In the brain,
however, the arteries were tortuous, hard, and were studded with miliary
aneurysms. It is not possible to judge accurately the state of the whole
arterial system by the stage of the lesion in any one artery; but on the
whole one may say that an undue thickening of the radial artery
indicates analogous changes in the mesenteric arteries and in the aorta.
So far as the anatomical lesions in the aorta and branches are
concerned, there is much uniformity even though the etiologic factors
have been diverse. The only difference is one of extent. To Thoma we owe
the first careful work on arteriosclerosis. He regarded the lesion in
arteriosclerosis as one situated primarily in the media; there is a lack
of resistance in this coat. His views are now chiefly of historical
interest. As the author understands him, he considered a rupture in the
media to be the cause of a local widening and consequently the blood
could not be distributed evenly to the organ which was supplied by the
diseased artery or arteries. Moreover, there was danger of a rupture at
the weak spot unless this were strengthened. It was essential for the
even distribution of blood that the lumen be restored to its former
size. Nature's method of repair was a hypertrophy of the subintimal
connective tissue and the formation of a nodule at that point. The
thickening was compensatory, resulting in the establishment of the
normal caliber of the vessel. Thoma showed that by injecting an aorta in
the subject of such changes, with paraffin at a pressure of 160 mm. of
mercury, these projections disappeared and the muscle bulged externally.
He recognized the fact that the character of the artery changed as the
years passed, and to this form he gave the name, primary
arteriosclerosis. To the group of cases caused by various poisonous
agents, or following high peripheral resistance and consequent high
pressure, he gave the name, secondary arteriosclerosis. This is a useful
but not essential division, as the changes which age and high tension
produce may not be different from those produced in much younger persons
by some circulating poison. And most important to bear in mind,
octogenarians may have soft, elastic arteries.
As the body ages, certain changes usually take place in the arteries
leading to thickening and inelasticity of their walls. This is a normal
change, and in estimating the palpable thickening of an artery, such as
the radial, the age of the individual must always be considered.
Thayer and Fabyan, in an examination of the radial artery from birth to
old age, found that, in general, the artery strengthens itself, as more
strain is thrown upon it, by new elastica in the intima and connective
tissue in the media and adventitia. Up to the third decade there is
only a strengthening of the media and adventitia. During the third and
fourth decades there is also distinct connective tissue thickening in
the intima. "In other words, the strain has begun to tell upon the
vessel wall, and the yielding tube fortifies itself by the connective
tissue thickening of the intima and to a lesser extent of the media." By
the fifth decade the connective tissue deposits in the intima are
marked, there is an increase of fibrous tissue upon the medial side of
the intima and, in lesser degree, throughout the media. "Finally, in
these sclerotic vessels degenerative changes set in, which are somewhat
different from those seen in the larger arteries, consisting, as they
do, of local areas of coagulation necrosis with calcification,
especially marked in the deep layers of the connective tissue
thickenings of the intima, and in the muscle fibers of the media,
particularly opposite these points. These changes may ... go on to
actual bone formation." The mesenteric artery differs in some respects
from the radial, but in the main, the changes brought about by age are
the same. Thayer and Fabyan note two striking points of difference: "(1)
calcification is apparently much less frequent than in the radials; (2)
in several cases plaques were seen with fatty softening of the deeper
layers of the intima and superficial proliferation--a picture which we
have never seen in the radial." (See Fig. 2.)
[Illustration: Fig. 2.--Cross-section of a coronary artery, x50, showing
nodular sclerosis. Note the heaping up of cells in the intima, the
fracture of the elastica, and the destruction of the media beneath the
nodule. The primary lesion evidently was in the media. The thickened
intima is the effort on the part of nature to heal the breach. At such
places as shown here aneurysms may form. (Microphotograph.)]
Aschoff's studies of the aorta show that, "in infancy the elastic laminae
of the media stand out sharply defined, well separated from each other
by the muscle layers, which are well developed.... From childhood there
is to be observed a slowly progressive increase in the elastic elements
of the media. Not only do the individual lamellae seen in cross-sections
become thicker, but also they afford an increasing number of fine
secondary filaments feathering off from these and crossing the muscle
layer, so that now they are no longer sharply defined, but more ragged
upon cross-section. This progressive increase attains its maximum at or
about the age of thirty-five, and from now on for the next fifteen
years the condition is relatively stationary. After fifty there is to be
observed a slowly progressive atrophy of the elastica. The media becomes
obviously thinner and presumably weaker." (Adami.) It has also been
found (Klotz) that after the age of thirty-five, the muscle of the media
begins to exhibit fatty degeneration which after fifty years is well
marked. The fatty degeneration may then give place to a calcareous
infiltration or the fibers may undergo complete absorption. It would
appear that the thinning of the aortic media is due not so much to the
atrophy of the elastic tissue as to that of the muscle tissue. The
elastic tissue does lose its specific property and the artery thus
becomes practically a connective tissue tube.
Scheel has made very careful measurements of the ascending, the
thoracic, and the abdominal aorta, and the pulmonary artery. He found
that from birth to sixty years, the aorta became progressively wider and
lost its elasticity. The pulmonary changed little, if at all, after
thirty to forty years, and where before it was wider than the aorta, it
now was found to be smaller. In chronic nephritis both were widened. The
continuous increase of width and length of the aorta stands in reverse
relationship to the elasticity of its walls.
Although the division of the lesions into nodular, diffuse, and senile
has been the usual one, it is better to separate three groups into (1)
nodular, (2) diffuse or senile, and (3) syphilitic. There is more known
about the histology of the syphilitic form and the lesions which consist
of puckerings and scars seen on opening an aorta just above the valves,
and on the ascending portion of the arch are characteristic. A
macroscopic examination suffices in most cases for a definite diagnosis.
In the nodular form the lesions are found on the aorta and large
branches particularly at or near the orifices of branching vessels.
These nodules may increase in size, forming rather large, slightly
raised plaques of yellowish-white color. They are, as a rule,
irregularly scattered throughout the aorta and branches and tend to be
more numerous and larger in the abdominal aorta. The initial lesion is
in the media, consisting of an actual dissolution of this coat with
rupture of the elastic fibers and infiltration with small round cells.
There is thus a weak spot in the artery. Hypertrophy of the intimal
cells takes place, layer upon layer being added in an attempt to
strengthen the vessel at the injured place. Coincidently with this,
there is thickening by a connective tissue growth in the adventitia. The
process begins, at least in syphilis, around the terminals of the vasa
vasorum. It will be recalled that the blood supply of the inner portion
of the media comes from within the vessel itself. As the intimal growth
increases, the blood supply is cut off. The inevitable result is
softening of the portion farthest from the lumen of the vessel. As a
rule there has been a sufficient growth of connective tissue in the
media and adventitia to repair the damage done to the media. This
softening and dissolution gives rise to a granular debris composed of
degenerated cells and fat. This is the so-called atheromatous abscess.
There are no leucocytes as in ordinary pus. These "abscesses" are
frequent and in rupturing leave open ulcers with smooth bases, the
atheromatous ulcer. A further change which often takes place is
calcification of the bases of the ulcers and calcification of the
softened spots before rupture takes place. This only occurs in advanced
cases. (See Fig. 3.)
[Illustration: Fig. 3.--Arteriosclerosis of the thoracic and abdominal
aorta, showing irregular nodules, atheromatous plaques, denudation of
the intima, thin plates of bone scattered throughout with spicules
extending into the lumen of the vessel. Note the contraction of the
openings of the large branches, the rough appearance of the aorta and
the greater degree of sclerosis of the upper two-thirds, i. e., of the
aorta above the diaphragm. This aorta in the recent state was much
thickened and almost inelastic.]
[Illustration: Fig. 4.--Arteriosclerosis of the arch of the aorta.
Numerous calcified plaques, thickening and curling of the aortic valves,
giving rise to insufficiency of the aortic valves. The aortic ring is
rigid and not much dilated. (Milwaukee County Hospital.)]
[Illustration: Fig. 5.--Normal aorta. Compare with Fig. 3. Note the
perfectly smooth, glossy appearance of the intima. The openings of all
the intercostal arteries are distinctly seen. In the recent state this
artery was highly elastic, capable of much stretching both transversely
and longitudinally.]
Rather contrary to what one would expect, there are no new capillaries
advancing from the media to the intima in the nodular form of
arteriosclerosis, consequently there is no granulation tissue to heal
and leave scars. It must be borne in mind that these changes rarely, if
ever, are the only ones found throughout the arterial system.
Nevertheless, the manifold changes, as will be shown within, appear to
be but stages of one primary process.
The character of the changes which are known as diffuse arteriosclerosis
seems to have, at first sight, little in common with those of the
nodular sclerosis. The aorta may or may not have plaques of nodular
sclerosis, while the arteries, such as the radial or temporal, may be
beaded or pipe stem in hardness. In spite of these far advanced
peripheral lesions the aorta may appear smooth but it is markedly
dilated, particularly the thoracic portion, it is noticeably thinned
even on macroscopic examination, it has elongated as evidenced by its
slight tortuosity, and it has lost the greater part of its elasticity.
The abdominal aorta is not so extensively affected, although this, too,
shows some elongation and slight thinning. This is considered by some
pathologists to be the uncomplicated form of the so-called senile
arteriosclerosis. It is more of the nature of a degenerative change, it
is true, but, as will be shown later, it has its beginnings, at times,
in comparatively young persons and its etiology is not simple. This
type has been studied most carefully by Moenckeberg, who showed that on
the large branches of the aorta there were depressions due to a
degeneration of the middle coat. These depressions encircled the vessel
to a greater or lesser extent, causing small bulgings at such places
and giving to the vessel a beaded appearance. On viewing such an artery
held to the light, the sacculated spots are seen to be much thinner than
the contiguous normal artery. Associated with such changes in the aorta
and large branches is marked sclerosis of the smaller arteries. Intimal
fibrosis is common, together with hypertrophy and fibrosis of the middle
coat. Not infrequently periarterial thickening is also seen.
Calcification of the media is found and is said to be preceded by
hypertrophy of the middle coat.
Pure cases of this, the so-called Moenckeberg type, are seen but seldom.
Most commonly there are nodules and plaques in the aorta and large
branches together with thinning and sacculation of other portions of the
vessels' walls. While the two processes appear at a glance to be so
different from each other, it is possible for them to have a common
origin. The initial lesion is in the media but the resulting sclerotic
changes depend upon the kind of vessel, the strength of the coats, the
pressure in the vessel, and other causes.
Thus the sclerosis of the radials of such an extent that these arteries
are easily palpable, appears to be a different process from that of the
sclerosis in the aorta, yet fundamentally it is the same. The difference
lies in the anatomic structure of the two vessels, and possibly also in
the degree of stretching and strain to which the vessels are subjected
at every heart beat. In the radial artery the media as usual is affected
first. The muscle cells undergo degeneration and either marked
thickening takes place or sacculation results, depending upon the
severity of the exciting cause. Calcification of the media is common.
This occasionally takes the form of rings encircling the vessel, and
gives to the examining finger the sensation of feeling a string of fine
beads. There may be calcification of the subintimal tissue without
deposits of lime salts in the media, but this is more commonly found in
the larger arteries. When the calcification occurs in plates through the
media, the well known pipe stem vessel is produced. (Fig. 6.)
[Illustration: Fig. 6.--Radiogram of a man aged seventy-five, showing
calcification of both radial and ulnar arteries.]
The senile sclerosis found in old people is usually a combination of the
Moenckeberg type in the large and medium-sized arteries, and the nodular
type in the aorta, leading eventually to calcareous intimal deposits,
and widened, elongated, inelastic aorta.
=Syphilitic Aortitis=
[Illustration: Fig. 7.--Syphilitic aortitis of long standing. The aortic
valves are curled and thickened, the heart is enlarged and the cavity of
the left ventricle is dilated. (Milwaukee County Hospital.)]
The seat of election of the syphilitic poison is in the aorta just above
the aortic valves, Fig. 7, and in the ascending portion of the arch.
There are semitranslucent, hyaline-like plaques which have a tendency to
form into groups and, instead of undergoing an atheromatous change as
in the ordinary nodular form of arteriosclerosis, they are prone to scar
formation with puckering, so that macroscopically the nature of the
process may, as a rule, be readily diagnosed. Microscopically the
process is found to be a subacute inflammation of the media, which has
been called a mesaortitis. There is marked small celled infiltration
around some of the branches of the vasa vasorum and there appears to be
actual absorption of the tissue elements of the middle coat. This is
accompanied by hypertrophy of the intimal tissue. There follows
degeneration in the deeper portions of this new tissue and new
capillaries are formed which have their origin in the inflammatory area
in the media. As is everywhere the case throughout the body, granulation
tissue in the process of healing contracts and forms scars. This
explains the scar formation in the aorta. When the process is more
acute, instead of there being a reparative attempt on the part of the
intima, there is actual stretching of the wall at the weakened spot and
there results an aneurysmal dilatation. =Spirochetae pallidae= have been
found in the degenerated media and in small gummata which were situated
beneath the intima. Within the past years it has been found that a large
percentage of patients with cardiovascular disease give the Wassermann
reaction. In cases of aortic insufficiency, the reaction is present in
almost every case. This is in marked contrast to the cases of diffuse
endocarditis where the reaction is rarely present.
According to Adami the effects of syphilis upon the aorta are the
following: (1) the primary disturbance is a granulomatous, inflammatory
degeneration of the media; (2) this leads to a local giving way of the
aorta; (3) if this be moderate it results in a strain hypertrophy of the
intima and of the adventitia, with the development of a nodose intimal
sclerosis; (4) if it be extreme, there results, on the contrary, an
overstrain atrophy of the intima and aneurysm formation; (5) the intimal
nodosities are here not of an inflammatory type and are nonvascular,
although, with the progressive laying down of layer upon layer of
connective tissue on the more intimal aspect of the intima, the earlier
and deeper-placed layers of new tissue gain less and less nourishment,
and so are liable to exhibit fatty degeneration and necrosis; (6) these
products of necrosis exert a chemotactic influence upon the nearby
vessels of the medial granulation tissue, with, as a result, (a) a
secondary and late entrance of new vessels into the early and
deeply-placed atheromatous area, (b) absorption of the necrotic
products, (c) replacement by granulation tissue, (d) contraction of the
granulation tissue, and (e) depression and scarring of the sclerotic
nodules so characteristic of syphilitic sclerosis.
In the smaller arteries and arterioles the arteriosclerotic process
appears on superficial examination to be a different process from that
in the aorta and large arteries, but the difference is only apparent. It
will be recalled that there is relatively much more muscle tissue in the
arterioles than in the large arteries. The size, of course, is much
less. Large nodular plaques are not possible. The atheromatous
degeneration is not marked. In the smaller muscular arteries is seen the
intimal proliferation, the stretching of the Moenckeberg type, and the
calcification of the media rather than the intima. The media is thinned
beneath the marked intimal proliferation so that the artery exhibits
translucent areas when held to the light. Again, there is seen
degeneration of the muscle and replacement by connective tissue with or
without hypertrophy of the intima. In the arterioles three kinds of
changes occur: a muscular hypertrophy; a fibrosis of all the coats; or a
marked proliferation of the intimal endothelium. The last two are
probably the same process, the connective tissue having its origin in
the proliferated endothelial cells. Such a deposition of layer upon
layer of cells in an arteriole and the resulting fibrosis leads to the
condition of disappearance of the lumen of the vessel, endarteritis
obliterans. This obliterating endarteritis is not, of course, due alone
to syphilis. Syphilis is only a type of poison which produces such
changes as have been described above. It is in the organs such as the
kidney, liver, spleen, and intestines that one sees the most perfect
examples of this obliterating endarteritis. Endarteritis deformans is a
term applied to the condition of the arteries as a result of irregular
thickenings and deposits of lime salts in the walls. These changes give
rise to marked tortuosity of the vessels.
Occasionally such an obliterating process takes place in a larger
artery. A thrombus forms and by a process of central softening, new
channels permeate the thrombus, thus restoring to some extent the
function of the vessel.
That the same process leads at one time to thinning and at another time
to thickening of the arterial walls has been noted above. Prof. Adami
holds that the regular development of layer upon layer of new connective
tissue is non-inflammatory. He calls it a "strain hypertrophy." It is
analogous to the localized hypertrophy of bone where the muscle tendons
are attached, as is so frequently seen in athletes. The increased
tension on connective tissue, provided that it is not overstrained,
leads to its overgrowth, but only when there is sufficient nourishment.
Such conditions are adequately fulfilled in the arteries. When a local
giving way under pressure occurs in the media, the intima is put on the
stretch (see Fig. 8), and there results a hypertrophy of the intima
until the volume of the new tissue and the resistance which this affords
to the mean distending force, balances the loss sustained by the
weakened media. When the balance is struck, the hypertrophy is arrested.
The youngest tissue is thus found directly beneath the endothelium. Now
should this local weakening of the media have an acute origin, instead
of a stimulus to growth there is overstrain, and there is, in
consequence, not hypertrophy but atrophy. The beginning process is here
a mesaortitis, but the acuteness of the poison, and the pressure from
within the artery so stretches the artery that there is no compensatory
hypertrophy, but a thinning, and the ground is prepared for aneurysmal
dilatation or pouching.
[Illustration: Fig. 8.--I, media weakened at M' with overgrowth of
intima filling in the depression. II, with postmortem rigor and
contraction of the muscles of the media and removal of the blood
pressure from within, the stretched media at M'' contracts; the intimal
thickening thus projects into the arterial lumen. (After Adami.)]
Again, one not infrequently encounters intimal nodosities when the
underlying media appears of normal thickness. The explanation of this
apparent exception is that the media in the living aorta is actually
thinned, but the layers of subintimal tissue deposited over the weak
spot due to strain hypertrophy become bulged inward when the pressure is
relieved, as at postmortem. The media has not lost all of its elasticity
(see Fig. 9), hence it contracts and there is the appearance of a nodule
on the intima beneath which is a media equal in thickness to that of the
healthy surrounding media.
[Illustration: Fig. 9.--Schematic representation of the increased strain
brought to bear upon the cells of the intima, Int., when the media,
Med., undergoes a localized expansion through relative weakness. (After
Adami.)]
The essential lesion in arteriosclerosis of the aorta and large arteries
is a degeneration in the middle coat. This may be brought about by a
variety of poisons circulating in the body. In syphilis, for example,
the initial lesion has been shown to be a mesaortitis. The media seems
to be dissolved, the artery is consequently thinned, there is actual
depression along the level of the vessel. The elastic fibers disappear
and small-celled infiltration takes its place. The intima hypertrophies,
layer upon layer being added in an attempt to restore the strength of
the vessel. There is also, as a rule, rather pronounced hypertrophy of
the adventitia.
=Experimental Arteriosclerosis=
Within the past few years many workers have attempted by various means,
to produce arterial lesions in animals, chiefly rabbits and dogs. The
present status is somewhat chaotic, some affirming and some denying that
arterial changes follow the various methods employed. Following the
injection of small, repeated doses of adrenalin over a certain period of
time, changes occur in the arteries of rabbits which are
arteriosclerotic in type, the essential lesion being a degeneration of
the muscular and elastic tissue of the media with the consequent
production of aneurysm in the vessel. This is said by some to be quite
like the type of arteriosclerosis in man which has been so well
described by Moenckeberg. The degenerations in the arteries following
the experimental lesions are of the nature of a fatty metamorphosis, and
later proceed to calcification. Barium chloride, digitalin,
physostigmin, nicotin and other substances, as well as adrenalin, have
been found to exert a selective toxic action on the muscle cells of the
middle coat of the aorta. The infundibular portion of the pituitary
body, the portion which is developed from the infundibulum of the brain,
possesses an internal secretion, which, injected intravenously, causes a
marked rise of blood pressure and slowing of the heart beat. So far as I
know, this active principle of the gland has not been used in an attempt
to produce experimentally the lesions of arteriosclerosis.
Wacker and Hueck succeeded in producing aortic disease in rabbits which
they considered to be in many points quite like human arteriosclerosis.
They injected the rabbits intravenously with cholesterin. They feel that
this is of great importance in view of the fact that exercise (muscle
metabolism) dyspnea, certain poisons, as well as adrenalin, and even
adrenal extirpation occasion a high cholesterin content of the blood.
Anitschow's experiments are confirmatory. He fed rabbits on large
amounts of cholesterin-containing substances (yolk of egg, brain
tissue) and pure cholesterin and found changes in the intima and inner
portion of the media consisting of fatty infiltration between the muscle
and elastic fibres, advent of small round cells and large phagocytic
cells containing fat droplets of cholesterin esters. The elastic fibres
were dissolved, broken up into fibrillae and these seemed to be absorbed.
The internal elastic lamina as such disappeared and the inner layer of
the aorta fused with the middle coat. He considers these changes to be
quite analogous to those found in human aortas.
Oswald Loeb produced changes in the arteries of rabbits by feeding them
sodium lactate (lactic acid). His controls fed on other acids became
cachectic, but showed no arterial changes. He further found that in 100
gm. of human blood there was normally from 15 to 30 mg. of lactic acid.
After heavy work, he found as much as 150 gm. He considers that after
adrenalin or nicotin injections, the function of the liver is so
disturbed that lactic acid is not bound. The arteriosclerosis is
actually due to the presence of free lactic acid in the circulation. He
succeeded, also, in producing lesions of the intima in a dog fed for a
long time on protein poor diet, plus lactic acid and sodium lactate.
Another investigator, Steinbiss, fed rabbits on animal proteins only, a
diet totally foreign to their natural habits. He succeeded, however, in
keeping some alive for three months. He also tried various substances
and in the general conclusions says that no aortic changes could be
produced in animals kept in natural living conditions by any mechanical
means, increase of blood pressure, digital compression, hanging by hind
legs, etc. In infectious diseases, especially septic, widespread
sclerotic changes occurred in the aorta. A most suggestive conclusion in
this "the most important result of feeding rabbits with animal proteins
is, along with a constant glycosuria, disease of the aorta and
peripheral arteries which is identical with changes in the aorta
produced by injections of adrenalin. The degree of disease of the
circulatory system increases with the duration of the experiment."
By a small addition of vegetable to the protein diet, the lives of the
animals were prolonged at will. With this modification of the
experiment, the findings in the vessel walls were noticeably altered.
The changes affected chiefly the intima, to less degree the media, and
histologically were very much like human intimal disease.
I have been unable to produce the slightest arterial lesions in rabbits
by intravenous injections of lead. Frothingham had no success feeding
animals with lead. In a study of autopsy material from persons up to 40
years, who died of infectious disease, he found changes in the arteries
of those who had succumbed to infection with the pus cocci or to very
severe infectious disease. These changes were, however, localized, and
were not like those of the general diffuse arteriosclerosis.
Adler has recently reported experiments on dogs, to which he fed or
injected intravenously various substances supposed to induce
arteriosclerotic changes. He was unable to find any arterial lesions
comparable to human arteriosclerosis.
The difficulty experienced by experimenters is not surprising when the
character of the changes is considered. Arteriosclerosis is not an acute
process. In its very nature, it is of months' or years' standing, the
specific changes are of slow growth, and more in the nature of
degeneration. It would seem that a very careful study of the histories
of those with arteriosclerosis and a final examination upon the actual
tissue might eventually give us data for the etiology.
The most frequent site of disease in these experimental lesions is the
thoracic aorta, and it is there also that the most severe changes are
seen. While the toxic action is felt in the vessels all over the body,
the lesions are, as a rule, scattered and small. The thoracic aorta
stands the brunt of the high pressure, and this combined with the
poisonous action of the drug or drugs, results in the formation of a
fusiform aneurysmal dilatation which stops at the diaphragmatic opening.
The aortic opening in the diaphragm seems to act as a flood gate,
allowing only a certain amount of blood to flow through, and thus the
abdominal aorta is protected to a great extent from the deleterious
effects of increased pressure. Focal degenerative lesions are, however,
found in the abdominal aorta.
Changes somewhat analogous to those found in the human aorta as the
result of intimal proliferations, are produced in animals by the toxins
of the typhoid bacillus and the Streptococcus pyogenes. Clinically,
Thayer and Brush have found that the arteries of those who have
recovered from an attack of typhoid fever are more palpable than the
arteries of average individuals of equal age who have never had the
disease.
Experimentally, the changes caused by the toxins above noted are
proliferations of cells in the intima and subintimal tissues, and a
breaking up of the internal elastic laminae into several parallel layers
which stretch themselves among the proliferating cells. The diphtheria
toxin, on the contrary, produces a lesion more like that caused by
adrenalin. All pathologists are not agreed as to whether the
experimental lesions produced by blood pressure raising drugs are
similar to the arteriosclerotic changes in the arteries of man.
Some of the work on rabbits has been discredited for the reason that
arteriosclerosis appears spontaneously in about fifteen per cent of all
laboratory rabbits. Furthermore, comparatively young rabbits have been
found with arteriosclerosis. O. Loeb, however, denies this. He has
examined in the course of eight years 483 healthy rabbits and never
found arterial changes. The spontaneous lesions can not be distinguished
histologically from those due to adrenalin. They differ macroscopically
in that the lesion is usually limited to a few foci near the origin of
the aorta.
Lesions produced by the drugs enumerated above represent one type of
experimental arteriosclerosis. More interesting and important are the
experiments which seem to show that high tension alone is capable of
producing lesions in arteries which in all respects correspond to
Adami's strain hypertrophy and overstrain theory. It has been shown that
when a portion of vein is placed under conditions of high arterial
pressure, as in a transplantation of a portion of vein into a carotid
artery, the vein undergoes marked connective tissue hypertrophy which
includes all the coats. This is evidently strain hypertrophy. Again, it
has been demonstrated that by suspending a previously healthy rabbit by
the hind legs for three minutes daily over a period of three to four
months, there results hypertrophy of the heart with thinning and
dilatation of the arch and the upper part of the thoracic aorta. No
change was found in the abdominal aorta. The carotids, however, were
larger than normal and they showed typical intimal sclerosis with
connective tissue thickening.
Neither I nor others have been able to confirm this experiment, so it is
very doubtful whether mechanical pressure alone can produce true
arteriosclerosis. Some evidence is adduced to bear on this point,
however, in the fact that sclerosis of the pulmonary artery follows
often upon mitral stenosis. Yet we do not know but that factors other
than pressure alone produce the arteriosclerotic change in such cases,
so we are forced back on our conclusion expressed above; viz., that
experiments on animals fail to sustain the purely mechanical origin of
arteriosclerosis.
The changes in the intima constitute the effort on the part of nature to
repair a defect in the vessel wall which is to compensate for the
weakened media and the widened lumen. This applies only to true
arteriosclerosis, not to the condition produced experimentally by the
toxin of the typhoid bacillus, for example.
When an artery loses its elasticity and begins to have connective tissue
deposited in its walls, the pressure of the blood stretches the vessel
which is now no longer capable of retracting when the pulse wave has
passed, and, in consequence, the artery is actually lengthened. This
necessarily causes a tortuosity of the vessel which can be easily seen
in such arteries as the temporals, brachials, radials, and other
arteries near the surface of the skin.
The exact mechanism of increase of blood pressure is not satisfactorily
explained. The smaller arteries all over the body are supplied with
vasoconstrictor and vasodilator nerve fibers from the sympathetic
nervous system. Normally when an organ is actively functionating the
vessels are widely dilated and the flow of blood is rapid. Among the
many factors which influence blood pressure and blood supply must be
reckoned the psychic.
We know that normally there is a certain resistance offered to the
propulsion of blood through the arteries by the contraction of the
heart. This tonus is essential to the maintenance of an equalized
circulation. The muscular arterioles throughout the body by their tonus
serve to keep up the normal blood pressure and to distribute the blood
evenly to the various organs. Contraction of a large area of arterioles
increases the blood pressure and, strangely enough, the arteries respond
to increased arterial pressure, not by dilatation, but by contraction.
It would appear that rise of blood pressure tends to throw increased
work upon the musculature of the arterioles. This may be sufficient only
to cause them to hypertrophy, but further strain may easily lead to
exhaustion and to dilatation. "As a result strain hypertrophy of the
intima shows itself with thickening, and it may also be of the
adventitia, resulting in chronic periarteritis. And now with continued
degeneration of the medial muscle in those muscular arteries, fibrosis
of the media may also show itself. I would thus regard muscular
hypertrophy of the arteries and fibrosis of the different coats as
different stages in one and the same process. Whether these peripheral
changes are the more marked, or the central, depends upon the relative
resisting power of the elastic and muscular arteries of the individual
respectively." (Adami.)
[Illustration: Fig. 10.--Cross-section of a small artery in the
mesentery. Note that the vessel appears capable of being much widened.
The internal elastic lamina is thrown into folds somewhat resembling the
convolutions of the brain. Note also that the middle coat of the artery
is composed almost entirely of muscle. The enormous number of such
vessels in the mesentery and intestines explains the ability of the
splanchnic area to accommodate the greater part of the blood in the
body. Universal constriction of these vessels would naturally render the
intestines anemic. The vasomotor control of these vessels plays an
important role in the distribution of the blood. Small arteries in the
skin and in other organs, possibly the brain, have a similar function.
(Microphotograph, highly magnified.)]
It is conceivable that in one section of the body the vessels may be
markedly contracted, but if there is dilatation in some other part there
will be no increased work on the part of the heart, and theoretically,
there should be no rise of blood pressure. The vascular system, however,
while likened to a system of rubber tubes, must be regarded as a very
live system, every subsystem having the property of separate control.
For blood tension to be raised all over the body, conditions must favor
the generalized contraction of a large area of arterioles. Some authors
consider that the so-called viscosity of the blood also is a factor in
the causation of increased tension. The usual cause for the high tension
is probably the presence in the blood of some poisonous substance.
It is held by some authors that the great splanchnic area is capable of
holding all the blood in the body and in respect of its liability to
arteriosclerosis, it is second only to the aorta and coronary arteries.
The enormous area of the skin vessels could probably contain most of the
blood. The tone of the vasoconstrictor center controls the distribution
of blood throughout the body. The fact that the vessels in the
splanchnic area are frequently attacked by sclerotic changes means, as a
rule, increase of work for the heart.[1] The resistance offered to the
passage of the blood must be great and signifies that, for blood to
travel at the same rate that it did before the resistance set in, more
power must be expended in its propulsion. In other words, the heart must
gradually become accustomed to the changed conditions, and, as a result
of increased work, the muscle hypertrophies. (See Fig. 11.)
[1] Longcope and McClintock, however, conclude that permanent
constriction of the superior mesenteric artery and celiac axis, as well
as gradual occlusion of one or both of these vessels, may be present in
dogs for at least five months without giving rise to definite and
constant elevation of blood pressure or to hypertrophy of the heart.
Further, they have been unable to find at autopsy on man a definite
association between sclerosis of the abdominal aorta and great
splanchnic vessels and cardiac hypertrophy.
[Illustration: Fig. 11.--Enormous hypertrophy of left ventricle probably
due to prolonged increased peripheral resistance. Note that the whole
anterior surface of the heart is occupied by the left ventricle. The
right ventricle does not appear to be much affected. x2/3.]
In diffuse arteriosclerosis accompanied by chronic nephritis the heart
is always hypertrophied. This is a result, not a cause of the
condition. In the pure type, there is hypertrophy only of the left
ventricle without dilatation of the chamber. The muscle fibers are
increased in number and in size, and there are frequently areas of
fibrous myocarditis due to necrosis caused by insufficient nutrition of
parts of the muscle. In these cases the coronary arteries share in the
generalized arteriosclerotic process. The openings of the arteries
behind the semilunar valves may be very small. There is often thickening
and puckering of the aortic valves and of the anterior leaflet of the
mitral valve leading, at times, to actual insufficiency of the orifice.
Later, when the heart begins to weaken, there is dilatation of the
chambers and loud murmurs result, caused by the inability of the
nondistensible valves to close the dilated orifices. Until the
compensation is established, it is impossible to say whether or not true
insufficiency is present.
In senile arteriosclerosis there is the physiologic atrophy of the media
to be reckoned with. This change has already been referred to. When such
degeneration has taken place, the normal blood pressure may be
sufficient to cause stretching of the already weakened media with or
without hypertrophy of the intima. The arteries may be so lined with
deposits of calcareous matter that they appear as pipe stems. More
frequently there are rings of calcified material placed closely together
or irregular beading, giving to the palpating finger the impression of
feeling a string of very fine beads. The arteries are often tortuous,
hard, and are absolutely nondistensible. At times no pulse wave can be
felt.
The larger arteries such as the brachials and femorals are most
affected. The walls become thinned and show cracks, and areas
apparently, but not actually denuded of intima. Yellowish-white,
irregular, raised plaques are scattered here and there. Interspersed
among these areas are irregularly shaped clean-cut ulcers having as a
rule a smooth base, and frequently on the base is a thin plate of
calcified matter. The color of these denuded areas is usually brownish
red or reddish brown. White thrombi may be deposited on these areas. The
danger of an embolus plugging one of the smaller arteries is great and
probably happens more often than we think. The collateral circulation is
able to supply the thrombosed area. Should the thrombus be on the
carotid arteries, hemiplegia may result from cerebral embolism. On
microscopic examination of the arteries there is seen extreme
degeneration of all the coats, the degeneration of the media leading
almost to an obliteration of that coat. On seeing such arteries as these
one wonders how the circulation could have been maintained and the
organs nourished. Senile atrophy of the internal organs naturally goes
hand in hand with such arterial changes.
There is, as a rule, no increase in arterial tension; on the contrary,
the pressure is apt to be low. This is readily understood when the heart
is seen. This organ is small, the muscle is much thinned, it is flabby
and of a brownish tint, the so-called "brown atrophy." Microscopically,
there is seen to be much fragmentation of the fibers with a marked
increase of the brown pigment granules which surround the cell nuclei.
Cases are seen, however, in which blood pressure increases as the
patient grows older. The hearts in such cases are more or less
hypertrophied and show extensive areas of fibroid myocarditis.
From what has been said, it follows that hypertension alone may be the
cause of arteriosclerosis; that certain poisons in the blood which
attack the media and cause it to degenerate and weaken cause
arteriosclerosis without increased blood pressure; that the normal blood
pressure may be, for the artery which is physiologically weakened in an
individual over fifty, really hypertension, and arteriosclerosis may
result. Our observations lead us to believe that the process is at
bottom one and the same. The different types noted clinically depend
upon the nature of the etiologic factors and the kind of arterial tissue
with which the individual is endowed. This view at least brings some
order out of previous chaos, and corresponds well with our present
knowledge of the disease.
There are many cases of arteriosclerosis which lead to definite
interference with the closure of the valves of the heart, particularly
the aortic and the mitral. It has been said that puckerings of the
valves frequently occur (Fig. 12). This arteriosclerotic endocarditis at
times leads to very definite heart lesions, chiefly aortic or mitral
insufficiency, or both with, at times, murmurs of a stenotic character
at the base. There is rarely true aortic stenosis, however. The murmur
is caused by the passage of the blood over the roughened valves and into
the dilated aorta. Aortic stenosis is one of the rarest of the valvular
lesions affecting the valves of the left heart, and should be diagnosed
only when all factors, including the typical pulse tracings, are taken
into consideration.
[Illustration: Fig. 12.--Aortic incompetence with hypertrophy and
dilatation of left ventricle, the result of arteriosclerosis affecting
the aortic valves. Note how the valves have been curled, thickened, and
shortened, the edges of valves being a half inch below the upper points
of attachment. The anterior coronary artery is shown, the lumen
narrowed. (Reduced one-half.)]
The kidneys, as a rule, show extensive sclerosis. They are small, firm,
and contracted and not always to be differentiated from the contracted
kidneys of chronic inflammation. The lesions of the arteriosclerotic
kidney are due to narrowing and eventual obstruction of the afferent
vessels. The organs are usually bright red or grayish red in color. At
times there is marked fatty degeneration of cortex and medulla, giving
to them a yellowish streaking. The capsule is here and there adherent,
the cortex is much thinned and irregular. The surface presents a
roughly granular appearance. The glomeruli stand out as whitish dots
and the sclerosed arteries are easily recognized, as their walls are
much thickened. The process does not, as a rule, affect the whole kidney
equally, but rather affects those portions corresponding to the
interlobular arteries. The replacement of the normal kidney tissue by
connective tissue and the resulting contraction of this latter tissue
leads to the formation of scars. As the process is not regular, the
scarring is deeper in some places than in others, with the result that
localized rather sharply depressed areas appear on the surface. The
pelvis is relatively large and is filled with fat. The renal artery is
often markedly sclerosed and the whole process may be due to localized
thickening of the artery, or as part of a general arteriosclerosis. The
latter is the more frequent. Microscopically, it is seen that the
tubules are atrophied, the Bowman's capsules are, as a rule, thickened,
and the glomeruli are shrunken or have been replaced by fibrous tissue.
In places they have fallen out of the section. There is marked
proliferation of connective tissue in cortex and medulla. The arterioles
are thickened, the sclerosis being either of the intima or media or of
both. There is even occlusion of many arterioles.
Changes in other organs as the result of arteriosclerosis of their
afferent vessels occur, but are not so characteristic as in the kidney.
In the brain the result of gradual thickening of the arterioles is a
diminished blood supply, softening of the portion supplied by the
artery, and later a connective tissue deposit. The occurrence of thrombi
is favored and, now and again, a thrombus plugs an artery which supplies
an important and even vital part of the brain. The arteries of the brain
are end arteries, hence there is no chance for collateral circulation.
It is therefore evident how serious a result may follow the disturbance
in or actual deprivation of blood supply to any of the brain centers or
to the internal capsule.
=Arteriosclerosis of the Pulmonary Arteries=
There have been a number of cases of sclerosis of the pulmonary
arteries, either alone, or associated with general systemic
arteriosclerosis.
A primary and a secondary form are recognized, the former in conjunction
with congenital malformations of the heart, the latter as the result of
severe infection or of mitral stenosis. These two causes seem to be the
most important in the production of the arterial changes. The cases thus
far described have revealed widespread thickening of the pulmonary
arteries. If one may judge by the description of the pathologic changes,
the condition is quite similar to that produced in a vein by
transplantation along the course of an artery. The diffuse form with
connective tissue thickening of all coats has been generally described.
There is also obliterating endarteritis of the smaller vessels. In the
etiology of the condition severe infection seems to play a prominent
role. The constant presence of right ventricular hypertrophy is
interesting, the heart dullness extends, as a rule, far to the right of
the sternum. In some of the cases no demonstrable changes were observed
in the bronchial arteries or in the pulmonary veins.
Sanders has described a case of primary pulmonary arteriosclerosis with
hypertrophy of the right ventricle.
Recently Warthin[2] has reported a case of syphilitic sclerosis of the
pulmonary artery which places the lesion in exactly the same category as
that of syphilis in the systemic arteries. There was also aneurysm of
the left upper division present and, to settle the etiologic nature of
the process, Spirochete pallida were found in the wall of the aneurysm
sac and in that of the pulmonary artery. The microscopic picture in the
pulmonary artery could not be told from that in a syphilitic aorta.
[2] Warthin, A. S.: Am. Jour. Syph., 1918, i, 693.
=Sclerosis of the Veins=
Phlebosclerosis not infrequently occurs with arteriosclerosis. It is
seen in those cases characterized by high blood pressure. Such increased
pressure in the veins is due, for example, to cirrhosis of the liver
which affects the portal circulation, or to mitral stenosis which
affects the pulmonary veins. The affected vessels are usually dilated.
The intima shows compensatory thickening especially where the media is
thinned. As a rule all the coats are involved in the connective tissue
thickening. Occasionally hyaline degeneration or calcification of the
new-formed tissue is seen. "Without existing arteriosclerosis the
peripheral veins may be sclerotic usually in conditions of debility, but
not infrequently in young persons." (Osler.)
In many cases of arteriosclerosis, the pathologic changes are not
confined to the arteries, but are found in the veins as well as in the
capillaries. Such cases could be called angiosclerosis.