The causes of arteriosclerosis are many and varied. No two persons have the same resisting power toward poisons that circulate in the blood. Some go through life exposed to all the infectious diseases without ever becoming infected, while others fall easy victims to every disease that comes, no matter how careful they may be, and it is quite the same in regard to the resistance of the arterial tissues. If the tubing is of first class quality and the individual does not place too much strain on it, he may live to the biblical three-score years and ten, and possess arteries which have undergone such slight changes that they are not palpable. Such a person is, however, the exception. On the other hand, if the tissue is of poor quality, even the ordinary wear and tear of life causes early changes in the vessels, and a person of forty may have hard arteries.

We have described in a previous chapter the changes which normally occur in the arteries as age advances. An artery that is normal for a man of fifty years would be distinctly abnormal for a boy of fifteen.

Two broad divisions of arteriosclerosis may be made: (1) congenital, or the result of inherited tendency; (2) acquired.

Congenital Form

When Dr. O. W. Holmes was asked how to live to the age of seventy, he replied that a man should begin to pick his ancestors one hundred years before he was born. Our parents determine the character of the tissues with which we start in life, and this determines our general resistance. We might properly speak of congenital arteriosclerosis where the affected individual had poor arterial tissue with which to begin life, for that, in a sense, is a congenital defect, and arterial tissue that is poor in quality is prone to disease.

The author is more and more impressed with the part that heredity plays in the determination of arterial degeneration. Especially does syphilis in the parents or grandparents leave its stigma in the succeeding generations in the shape of poor arterial tissue which is prone to early degeneration. Recently W. W. Graves has called attention to a malformation of the vertebral border of the scapula which consists in a concavity instead of the normal convexity of the bone. To this malformation he has given the name, scaphoid scapula. He considers this to be but one manifestation of a general lack of development in the individual. He speaks of this maldevelopment as a blight and considers that syphilis in the ancestors is responsible for the condition in the offspring. He finds that even in children, the subjects of the scaphoid scapula, the arteries are very definitely thickened. While confirmation of his observations is lacking, there is no doubt that we must lay the blame for much of the arteriosclerosis in our patients to the poor quality of arterial tissue transmitted by ancestors who have acquired some constitutional disease. It may have been syphilis, it may have been the degeneration produced by alcohol or other drug. We can not ignore the part which heredity plays. The various factors to be considered in the production of the acquired form of arteriosclerosis appear to me to be but contributory factors to a very great extent, the essential and fundamental factor being the quality of arterial tissue with which the individual is endowed.

Arteriosclerosis may occur in infants. Cases have been reported of calcification of the arteries in infants and children. The arteriosclerosis may occur without nephritis or rise of blood pressure. Cerebral hemorrhage in a child of two years has been seen. Heredity in these cases plays a most important rÔle. In many of the reported cases there was no question of congenital syphilis. Aneurysms, single or multiple, have been found in the arteries of children, and even the pulmonary artery may show sclerotic changes.

Acquired Form

As a rule the cases usually seen belong in this group because it seems as if a connection could be established almost always between one or more of the etiologic factors to be described and the disease. While this apparently is the case, we must never lose sight of the part which the quality of the tissue plays. When we leave this out of our calculations we undoubtedly make many false deductions. When two men of the same age who have been exposed to the same conditions as far as we can learn, are found to have quite different arteries, the one normal, the other thickened, we must postulate congenitally poor tissue on the part of the latter. Such tissue readily becomes diseased following conditions which would very likely have produced no noticeable effect on perfectly normal, healthy tissue.

Hypertension

Hypertension must still be reckoned with in the etiology of arteriosclerosis although the rÔle that it was thought to play does not seem so important. Changes of blood pressure alone are not considered by many to be sufficient for the production of arteriosclerosis. This may play some part, but there are many other factors mostly unknown which determine in any case the production of arterial lesions.

With every systole of the heart, blood is forced out into the arterial system against a certain amount of resistance represented by the tonicity of the capillary area, and the amount of cohesion between the viscous blood and the walls of arterioles. When a dilatation of the capillaries over any large area takes place, the blood pressure falls, provided there is no compensatory contraction in other areas to make up for the decreased resistance in the dilated vessels. The viscosity of the blood, as such, probably has very little effect on the resistance to the flow. With the systole of the heart there is a sudden dilatation of the arch of the aorta, and a wave of expansion follows, which is transmitted to the periphery and is lost only in the capillaries.

The blood pressure is constantly changing. Physiologically there are relatively wide variations in the pressure in a perfectly normal individual. There are some persons who have hypotension, a blood pressure much below the normal. Such persons have usually small hearts, small aortas, and they seem to have but little resistance to disease. Many diseases, especially the prolonged fevers, diminish markedly the blood pressure. Whether the hypertension is the cause of the structural changes that are found in the walls of the vessels, or is the result of the diminished area of the arterial tree through which the same amount of blood has to be driven as before the vessel walls became narrowed, is still disputed. As has been stated, experimental evidence would tend to place the initial blame upon the poisons circulating in the blood, which first damage the vessel walls. The subsequent changes then produce thickening and inelasticity. Some think (Allbutt) that the hypertension is primary. There are cases seen clinically that lend support to this view and there is experimental evidence also (v. Chap. II). Not infrequently individuals in middle life begin to show increase of arterial blood pressure without discoverable cause. In such case it may be that there is slowly progressing chronic nephritis. The urine if examined only superficially in single specimens may not reveal any abnormalities. Careful functional examination by means of the newer tests may reveal functional deficiency. It must not be supposed that all cases of increasing hypertension are cases of chronic nephritis. The opinion has already been expressed (Chap. III) concerning this point. Experience has convinced me that the opinion expressed in former editions is not altogether correct.

Age

No age is exempt from the lesions of arteriosclerosis if we consider the two groups. However, the disease is seen for the most part in persons past middle life. The relative frequency with which it is found in the different decades depends on so many factors that it is of no value to tabulate them. As has been stated, arteriosclerosis of all types is an involution process that advances with age. Longevity is a question of the integrity of the arterial tissue, and no one can tell what sort of "vital rubber" (Osler) any one of us has. However, many with poor tubing may make such use of it that it will outlast good tubing that is badly treated. Unfortunately we have no way of telling early enough with just what sort of arterial tissue we are starting life.

Sex

There is no doubt that men are far more prone to arterial disease than women are; all statistics are in accord on this point. This is explained by the greater exposure of men to those conditions of life which tend to produce circulatory strain, and so to produce arteriosclerosis, or vice versa. Arteriosclerosis in women is not often seen until after the fiftieth year. Cases of the most extreme grade of pipe stem arteries are, however, seen in old women, and calcified arteries are not hard to find among the inmates of an old woman's home.

Race

Some of the most beautiful examples of arteriosclerosis in this country are seen in the negro. Not only is this disease more frequent in the black race, but the age of onset is much earlier than in the Caucasian. The accidents of arteriosclerosis, viz., aneurysm, cerebral hemorrhage, etc., are more common among the negro males. The etiologic factors that are most often found in the history are the prevalence of syphilis and hard physical labor.

Occupation

Certain occupations have a distinct causal relationship to arteriosclerosis; among such are particularly those entailing prolonged muscular exercise, especially if much lifting is necessary. Every one is familiar with the phenomena accompanying the exertion of lifting. The breath is drawn in, the glottis is closed, and the muscles of the chest wall are held rigidly while the exertion lasts. This causes a great increase in blood pressure, and constant repetition of this will produce permanent high tension. In hospitals, the stevedores as a class have marked arteriosclerosis, and, almost without exception, they are comparatively young men. Occupations that are accompanied with prolonged mental strain, such as now occur to the heads of large manufacturing and financial institutions, also predispose to early arterial changes. Psychic activity, especially when it is accompanied by worry, is a potent factor in the production of the increased blood pressure which is the chief factor in producing arterial disease. It has been suggested that sexual continence in high-strung men produces changes in the nervous system which can conceivably lead to the production of high tension and further to arteriosclerosis. This, however, I can not think has any foundation in fact except in so far as such men are prone to live at high speed and wear themselves out sooner than the normal person. The sexual continence per se is not harmful. There are, however, men who seem not to be harmed by the constant wear and tear of our modern life. These are the exceptions.

Workers in factories where paint is made and the ingredients hand-mixed, are prone to develop arteriosclerosis early in life. It has been found that the laborers most apt to be victims of lead intoxication are those who are careless in their habits of cleanliness, particularly in regard to the fingernails. The continuous absorption of lead into the system, brings about a condition of hypertension that has its inevitable results.

The fact is that any occupation which entails either the absorption of toxic substances, or prolonged muscular labor, will hasten markedly the onset of arterial disease.

Food Poisons

The opinion that arteriosclerosis is due in large part to poisoning by end products or by-products of protein digestion is now receiving much support. Experiments on dogs and rabbits have lent some confirmation to chemical observations. It has been shown that dogs fed for a long time on putrefied meat developed inflammation and degeneration of the adventitia and media, with hyperplasia and calcification of the intima of many arteries. In the pulmonary and carotid arteries, in the vena cavas and myocardium, there were extensive necroses and hyaline degeneration. Moreover, injections of sodium urate and ergot caused necroses in the muscularis and elastica of the aorta, pulmonary artery, vena cavas inferior and heart muscle, but there was no calcification. Guinea pigs which were fed indol in small doses by the mouth over a long period showed atheromatous degeneration of the aorta.

Infectious Diseases

As more study has been given to the arteries in persons who have died of the acute infectious diseases, more has come to light concerning the effects of the toxins of these diseases on the vessel walls. In the arteries of children who have died of measles, scarlet fever, diphtheria, cerebrospinal meningitis, etc., degenerative changes in the arteries occur, modified only by the length of time that the toxins have acted.

Thayer has shown that the arteries of those who have passed through an attack of moderately severe or severe typhoid fever are as a rule more readily palpable than are the vessels of persons of corresponding years who have never had the disease. Clinically the typhoid toxin appears to cause the early production of arteriosclerosis. The changes in the arteries occur for the most part, and always earlier, in the peripheral arteries, and the media is chiefly affected. Minute yellowish patches are found on the aorta, carotids, and coronaries. In persons who have passed through an attack of one of the fevers, and have later died from some other cause, regenerative changes are sometimes found to have taken place in the arteries, consisting of an ingrowth of elastic fibers from the intact adventitia to the diseased media.

That there are some other factors than the infectious disease which are concerned in the production of arterial changes seems evident from a study[14] made recently among a group of almshouse inmates ranging in age from 38 to 90 years. The study included 500 persons of both sexes. Careful histories were taken to determine the presence of antecedent infectious disease. The radial artery was palpated to determine the presence of sclerosis. Among the cases giving a history of one infectious disease the following table gives the results:

A summary of the cases showed: 252 cases without sclerosis; 248 with sclerosis; 147 cases with infections but no sclerosis; 180 cases with infections and sclerosis.

This study failed to throw any positive light on the question. Infectious diseases undoubtedly play a certain rÔle, particularly those continuing a long time and certain particular infectious diseases, as measles.

Syphilis

Syphilis is one of the most important of the etiologic factors in the production of arteriosclerosis. It has been shown that in 85 per cent of cases of aortic insufficiency in persons, usually males, over forty-five years, who did not have chronic infective endocarditis, the Wassermann reaction was positive. Acute aortitis affecting the ascending and transverse portions of the arch of the aorta is very commonly seen, and the irregular, scattered, slightly raised, yellowish-white patches of sclerosis in the arch which are found years after the syphilitic lesion, are considered by some to be very characteristic of syphilis. Mesaortitis is the primary lesion and acts as a locus minoris resistentiÆ where an aneurysm forms.

Hypertensive cardiovascular cases have been serologically studied, and a positive Wassermann reaction found in a large percentage of one series. In fifty cases, 90 per cent either gave a positive Wassermann reaction or luetin test, were known to have syphilis, or had children with hereditary syphilis. This suggests what might be called "familial cardiovascular syphilis."

Hypertensive disease is possibly one of the common so-called "late" manifestations of syphilis. That syphilis is responsible for the arterial disease in the vessels of the brain, resulting in apoplexy or sudden cardiac death in middle life, has long been known. In fact, it is claimed (Osler) that all aneurysms occurring in persons under thirty years of age are due to syphilitic aortitis. In the late stages of syphilis the arterial lesions may be of a diffuse character.

Chronic Drug Intoxications

Lead, tobacco, and according to some, tea and coffee, are to be classed as causal factors in the production of arteriosclerosis. Certain it is that all these substances have a tendency to raise the arterial pressure, but whether the drug itself causes first a degeneration, and later a hypertension results, or vice versa, is not yet positively known. We have just mentioned that lead particularly has a marked effect in producing arterial lesions. Other drugs as adrenalin, barium chloride, physostigmin, etc., while producing experimental arteriosclerosis, hardly could produce the disease in man. Alcohol has been blamed for much, and as an etiologic factor in the production of arteriosclerosis formerly was accorded a first place. More recently much doubt has been thrown on this supposition by the work of Cabot, who showed that the mere drinking of even large quantities of spirits had no effect in producing arterial disease.

This observation has been recently substantiated by Hultgen, who carefully studied clinically 460 cases of chronic alcoholism. He says, "There are no cardiovascular symptoms which might be termed characteristic of chronic alcoholism, unless it be the peculiar fetal qualities of the heart sounds which we know as embryocardia. I find this very frequent among drinkers, but I can offer only a tentative explanation for it, namely the following: Embryocardia can only occur with low tension blood pressure, and in the absence of renal insufficiency. Hence it might be considered as a useful condition of no pathologic significance at all. That alcohol is a sclerogenic pharmakon and productive of arteriosclerosis with its usual train of symptoms may be a fact, but its demonstration would be difficult and is really not shown by my tabulations. There were cardiovascular changes, such as myocarditis, aortitis, valvular heart disease and arteriosclerosis in chronic alcoholics in 54.3 per cent of 461 cases, but this by no means constitutes a proof of the causal relationship between these lesions and the abuse of liquors. I believe it, nevertheless, to be good reasoning to ascribe the bulk of cardiovascular symptoms to the sclerogenic action of alcohol, while abstaining from an interpretation of its pathogenesis." Just what rÔle tobacco plays is difficult to say. My own opinion is, that of itself when used in moderation, it has no ill effects. However, as tobacco is a drug that may raise the blood pressure, excessive use must be held responsible for the production of arteriosclerosis. It is difficult to separate its effects from those produced by eating and drinking.

Overeating

There can be no doubt but that the constant overloading of the stomach with rich or difficultly digestible food is responsible for a large number of cases of arteriosclerosis. Every one must have noted the increase in force and volume of the heart beat after the ingestion of a large meal. The constant repetition of such processes conceivably can lead to damage to the vessel walls through hypertension.

In the metabolism of food in the intestines there are substances produced which are poisonous when absorbed directly into the circulation. Ordinarily these substances are rendered harmless either before absorption or are detoxicated in the liver to harmless substances. It is conceivable that a constant overproduction of such poisons would eventually damage the defensive mechanism of the body to such an extent that some of the poisons would circulate in the blood. An expression of a surplus of one, at least, of these decomposition products is the appearance of indican in the urine. It is not believed that indicanuria has the importance attached to it which some authors would have us believe. It is found too often and in too many varying conditions, nevertheless it undoubtedly does reveal the presence of perverted metabolism.

In how far the toxins absorbed from the intestinal tract are responsible for the production of arterial disease, it is not possible to say. Some observers lay great stress on this factor as a cause of arteriosclerosis. The author believes that the rÔle played by the absorption of products of perverted intestinal metabolism is an important one. The primary change is an increased tension in the arterioles which later leads to thickening of the coats of the vessels and to the other consequences of arterial disease. A vicious circle is thus established which has a tendency to become progressively worse.

Mental Strain

More and more does one become impressed with the fact that patients with arteriosclerosis are very often those who take life too seriously and either from ambition or from an exalted sense of duty lead especially strenuous lives. Not always are these persons addicted to drug or liquor habit. Many are rather abstemious in their habits. It is not so often that we see as a victim of arteriosclerosis, the carefree person who laughs his way through life without worrying about the morrow. He is not so prone to arteriosclerosis. Worry is a far more potent cause of breakdown than actual manual work. It is the rule to find thickened arteries among neurasthenics. This may be only part of a generalized degeneration of all tissue in the body. The blood pressure in such persons is usually low. So many men of our better class live under a continuous mental strain in the business world. The increase in arteriosclerosis cases is real, not apparent. The intense mental strain seems to cause a marked increase in blood pressure (for short periods of mental effort this has been proved) over a period of time sufficient to cause permanent changes in the vessel walls. The same sequence of events repeats itself; high tension, arterial strain, compensatory thickening, hypertrophied heart, etc.

Certainly the character of the arterial tissue has much to do with the determination of degenerative changes which may result from the action of one or more of the etiologic factors.

Muscular Overwork

Muscular overwork is to be reckoned with as an etiologic factor. One sees it especially among the laboring class in both whites and negroes. Possibly other factors, as alcohol and coarse heavy food, contribute to the early arterial degeneration. Hypertrophy of the heart occurs in athletes, and statistics gathered among the oarsmen especially, show a relatively high mortality at the different decades traceable to the high tension produced while in training. This question deserves more consideration than has been accorded it.

Renal Disease

Chronic disease of the kidneys (contracted red kidney) is one of the most certain producers of hypertension; in fact, some maintain that high tension, even without demonstrable kidney lesions, as revealed by careful urine examinations, is a valuable sign pointing to chronic nephritis. This is doubted by others, myself among them. Just what causes the increase in blood pressure sometimes to over 270 mm. of Hg, is not definitely known. It seems most probable that it is some poison elaborated by the diseased kidneys and absorbed into the general circulation. There it acts primarily on the musculature of the arterioles causing tonic contraction and an increase of work on the part of the heart to force the blood through narrowed channels. One fact is certain. We see patients in coma due to renal disease with blood pressure much over 200 mm of Hg. As these cases clear up, the pressure may fall, and should they seemingly recover, the recovery is accompanied with a marked decrease in blood pressure, finally reaching the normal for the individual. Moreover, in the course of a severe acute or subacute nephritis, hypertension is associated with headache, partial or total blindness, and drowsiness. When the pressure is reduced, all these symptoms disappear.

There is also the chronically shrunken and scarred kidney known pathologically as the arteriosclerotic kidney. It is probable that there are two groups of cases which we may designate: (1) primary; (2) secondary. In the primary group the kidney disease antedates the sclerosis of the arteries, and the sclerosis is most probably dependent on the constant high tension. We know that prolonged hypertension will produce severe forms of arteriosclerosis. The arterial disease in this group is caused by the renal disease.

In the second group the kidney changes are apparently due to the general arteriosclerosis which, affecting the kidney vessels, causes changes leading to atrophy and subsequent fibrous tissue ingrowth of scattered areas. These cases are not necessarily associated with hypertension; on the contrary there is more apt to be hypotension. Where the first group occurs for the most part in young and active middle-aged people, the second group is the result of involutionary processes which accompany advanced age.

However careful a urinalysis may be, there is no assurance that one can predict the pathologic state of the kidney. Often so-called normal urine will be secreted by a badly diseased kidney, whereas a urine which contains considerable albumin and many casts may be secreted by a kidney which is only temporarily the seat of inflammation. What matters after all is not the state of the kidney which the pathologist describes, but the actual functional response of the kidney in the body to the various tests now well known.

Ductless Glands

At the present time the tendency among some writers is to make the ductless glands the responsible agents in almost all diseases. Arteriosclerosis is no exception to this tendency. Sajous, for example, divides the morbid process producing arteriosclerosis into three types; (1) autolytic, (2) adrenal, (3) denutrition. In the first type he finds the pancreas to be the most important gland. It supplies an internal secretion which "takes a direct part in the protein metabolism of the tissue cells, and also in the defensive reactions within these cells, as well as in the phagocytes and in the blood stream." This being the case exaggeration of this digestive process has tissue destruction as its result, arteriosclerosis among them.

In the adrenal type Sajous argues that adrenalin produces lesions experimentally, therefore the adrenal gland has a profound influence by its internal secretion in connection with the sympathetic system in producing degenerations leading to arteriosclerosis.

The denutrition type has as its particular gland the thyroid. The sclerotic process in the arteries is due to the lack of thyroid as in cases of myxedema. After a long rÉsumÉ of his ideas he concludes "that arteriosclerosis is the result of excessive or deficient activity of certain ductless glands, the thyroid and adrenal in particular."

No one can dogmatically deny the part which the ductless glands may play in the production of arteriosclerosis, but it hardly seems that there is enough actual experimental evidence to show that they take such an important part as Sajous believes. Until further and more convincing evidence is offered by competent investigators, I prefer to look with some skepticism upon the ductless gland theory of the causation of arteriosclerosis. The field lends itself too easily to speculation and imagery. Some are already allowing themselves the mental debauch of this nature.