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 succ.u.mbed 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 a.n.a.logous 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 const.i.tute 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 pa.s.sed, 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 advent.i.tia, 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.)

[Ill.u.s.tration: 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 pa.s.sage 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 a.s.sociation between sclerosis of the abdominal aorta and great splanchnic vessels and cardiac hypertrophy.

[Ill.u.s.tration: 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 pa.s.sage 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.

[Ill.u.s.tration: 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 a.s.sociated 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.

CHAPTER III

PHYSIOLOGY OF THE CIRCULATION

No attempt will be made to cover the entire subject of the physiology of the circulation. Only in so far as it relates to arteriosclerosis and blood pressure and has a bearing on the probable explanation of blood pressure phenomena will it be discussed.

"The heart and the blood vessels form a closed vascular system, containing a certain amount of blood. This blood is kept in endless circulation mainly by the force of the muscular contractions of the heart; but the bed through which it flows varies greatly in width at different parts of the circuit, and the resistance offered to the moving blood is very much greater in the capillaries than in the large vessels.