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.)

Aschoff's studies of the aorta show that, "in infancy the elastic laminÆ 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 lamellÆ 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.)

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.)

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

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. SpirochetÆ pallidÆ 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.

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.

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 fibrillÆ 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 laminÆ 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.)

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.)

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.

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 rÔle. 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.

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.