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Dr. WRIGHT. During the past few years we have appeared before this committee and before the Senate committee requesting funds for research in the field of heart and blood-vessel diseases. I thought I would preface my request and presentation of need by a brief mention of some of the advances which have taken place within the last year or two and which have been in part or in whole subsidized by grants which have been appropriated as a direct result of the interest of Congress.

Mr. FOGARTY. That is good.

Dr. WRIGHT. These advances have been in many areas and they have frequently been basic but in such a modest degree in each year that the public generally is not aware of their presence nor of their significance until they culminate in what might be considered to be a breakthrough which is in terms of application to the care of human beings. I cannot stress too greatly, however, that the basic advances which are not given public notice for some years are frequently the most important steps in this overall picture.

But to mention a few things which have met the public attention in the last year or so, I think we should perhaps start with the advances in heart surgery. Most of the American public is familiar with the fact that it is possible now to do very successful surgery for several conditions involving the heart, such as certain types of congenital heart disease and operations on the mitral valve.

Operations on the aortic valve, which may be equally important to the patient, have been much more difficult. In the past an attempt has largely been made to substitute by means of insertion of a plastic valve the function of the aortic valve, but within the last month or so a successful operation has been done attacking the aortic valve itself directly, by Dr. Lillehei and his coworkers at the University of Minnesota.

This has been made possible because of advances in technique in what is known as open heart surgery. In other words, even up to a year or so ago heart surgery, while it was a great advance over anything accomplished before, was only possible by having the doctor put his finger in the heart of the patient and, in what might be called a blind way but with the trained perception of touch, rupture a valve either with the finger alone or with the use of a knife which was introduced along the finger.

The open heart technique is possible now because of developments in the way of so-called heart-lung preparations which permit the surgeon to bypass the heart and in that way work in a relatively dry field, where he is able to open the heart and examine to see what he should do and can do.

This has made it possible to close openings between the two sides of the heart which was not possible before—these are abnormal openings I am referring to—and finally to reconstruct successfully an aortic valve. This work of Dr. Lillehei's has largely been supported by grants from the United States Public Health Service under the congressional grant.

There have been large areas of progress in the substitution of grafts of synthetic materials for blood vessels such as the aorta and the iliac and other somewhat smaller vessels and now we are able to use grafts made of synthetic materials, as I mentioned before, instead of having to depend upon securing a satisfactory graft and preserving it well

enough from some other human being. These plastic grafts are being perfected and being used to a greater degree all the time and in a much more satisfactory way.

Much of this work is going on in institutions and with groups who are working under grants from the United States Public Health Service.

Another area that has been developed is a continuation of the study of cerebrovascular diseases. Whereas a few years ago very little attention was being paid to strokes except to express sympathy to the patient and his family, today there are a considerable number of institutions which have very active programs of research going on, including Harvard University, our own group at Cornell, the Mayo Clinic,

and others. Our own studies are being largely supported by United States Public Health grants and this is a large cooperative, long-term project in which Cornell University, Columbia University, New York University, Bellevue Hospital, the Rehabilitation Institute and numerous other ancillary services are involved in studying these patients and in subjecting them to controlled investigation to determine the worth of anticoagulant and rehabilitation treatment and in order to gain greater knowledge in the selection of the patients for which this would be suitable provided it proves to be of value.

The work seems encouraging, but it is still not in complete form.

I have here a report which has recently appeared in the Journal of the American Medical Association, which gives our 10-year experience in this field. This was before the grants of the Public Health Service came into this picture, but now this is being picked up and developed in a much more complete way as a result of the grants.

I might say that there have been new anticoagulants which have been developed and are now under additional study. Warfarin has been available for some years but for the first time now in this country one which was known as marcumar in Europe is now available under the term of liguamar and it has certain technical advantages over dicumerol and

some of the formerly used anticoagulants.

ANTICOAGULANT THERAPY

Also there have been developments in a new approach to anticoagulant therapy which includes an attempt at the dissolution of clots. The former anticoagulants, heparin, dicumerol and similar compounds, were largely directed at prevention of new clots or prevention of further extension of a clot which already existed, allowing the enzymes which naturally occur in the blood to take up the work of dissolving a clot which already existed, hoping that they wouldand they do for a fresh clot.

Mr. DENTON. You have something now that will dissolve a clot?

Dr. WRIGHT. Yes, sir; there are several substances now available which will dissolve clots. This does not mean that they are available for general distribution; far from it. One is plasmin with which groups have been working, one notable group at the Memorial Hospital, our own group and several others, and plasmin will produce a dissolution or dissolving of a clot. However, this has been studied for about 4 years now and it has not been possible for manufacturers to get it on a large scale and prepare lots which are consistent in

strength and completely free from the risk that an occasional lot may produce an untoward reaction such as fever, chills, and so forth.

At present it appears as though we are quite close to this. There is marked improvement in the material in the last 6 months but there is still what might be called a bug in the manufacture.

As you probably noted in the paper recently, Dr. Mario Stefanini in the Boston area has been working with a mold and using the principle of enzyme action as a result of purification of material from this mold. Dr. Stefanini is working under grants from the Heart Association and from the United States Public Health Service. He is a very quiet and sincere investigator and has been carrying on this work in a very conscientious way.

He released a little information about what he was doing in a modest way which was picked up by the press and given wide dissemination with implications which are not justified on the basis of the progress to date. I am not attempting in any way to belittle the work which he has done. I talked with Dr. Stefanini last Saturday over the phone and I have known him for years. He has been very embarrassed by this great publicity with an immediate demand for material to treat patients all over the country. Altogether he has a very small amount of this material and he is proceeding very cautiously with it as he should.

I merely mention, however, that it is possible that he may have something rather good here but on the other hand it may be several years before it becomes available for general use.

In the field of hypertensive agents very important progress has been made so that today we now have materials of several types used separately or together resulting in a very much better situation in terms of hypertension than has been present in the past. In the last year a significant breakthrough was made with a substance known as diuril which when used in conjunction with the older drugs of the serpentina group,

which have been discussed before you in previous years, adds a great deal to their effectiveness.

These are just examples, but they are very pertinent examples in terms of results of subsidized research which has been made possible or supported in a significant degree through grants from the United States Public Health Service.

ATHEROSCLEROSIS

Our needs are still very great. We need to know a good deal more about the fat or lipid chemistry of arteriosclerosis, or atherosclerosis, as we prefer to call it.

Mr. FOGARTY. What is the difference between the two?

Dr. WRIGHT. Arteriosclerosis is the common term used by most lay people, and it includes several different kinds of conditions affecting the arteries, some of which are much less serious than atherosclerosis. Atherosclerosis largely applies to the laying down of these lipid or fatty material and, later, calcium on the innermost lining of the arteries, producing the effect of narrowing the opening or lumen of the vessel to a point where it either closes off completely without clotting or allows a clot to form. This is a very serious situation. It results in the death of more people than any single mechanism affecting the human race. Therefore, it is No.1 on our priority list.

I am going to ask Dr. Andrus to discuss this in greater detail when he testifies, so we do not duplicate our testimony too much. However, we have had some experience with the use of substances which have been advocated to reduce the level of the cholesterol in the blood and with the implication, justified or unjustified, that this will in some way affect the amount of atherosclerosis in the vessel wall. The implication may be justified, but we do not have the full knowledge of that yet. It has been suggested that if patients

Mr. FOGARTY. What is the implication?

Dr. WRIGHT. The implication is that if you lower the cholesterol level in the blood you will necessarily improve the situation with reference to the deposit of chloesterol in the wall of the vessel. This may be true, and there is some evidence, as Dr. Andrus will develop, but we are not completely prepared to say we are going to lengthen life in any individual by forcing him to change his diet and lower his blood cholesterol 50 points or 40 points.

There are some substances, corn oil, safflower oil, peanut oil, fish oils, and others, which, when given, tend to decrease the level of the cholesterol in the blood. These are so-called unsaturated fats and, administered, they have been claimed to lower the cholesterol level in the blood.

The careful investigators who have demonstrated this have in each instance changed the diet by removing saturated fats, such as meat fat, dairy fat, and other saturated fats, from the diet, cutting the fat intake down to less than 20 percent of the diet as compared with the over 40 percent present in the average American diet.

In practice, however, the public, generally, and many physicians, have not done this in a thorough way, but the patient has taken the safflower oil or corn oil as a supplement instead of a substitute. I do not know how the final analysis of this will work out, but we have submitted a paper in which we ran very carefully controlled studies on medical students supplementing their regular diet with safflower oil. This was done as what is known as a double-blind test. We used an inactive substance for half the students and and safflower oil for the other half, and neither the physician administering this experiment nor the students knew which they were getting. At the end of 7 weeks, we switched the groups. They still did not know which they were getting, and we followed their cholesterol blood levels on a weekly basis. Upon termination of the experiment, all their blood cholesterols on the average were slightly higher than they had been at the beginning of the experiment. We are doubtful, at least as far as safflower oil goes, that, taken as a supplement in the amount of 75 cubic centimeters a day in addition to a regular diet, it will lower the cholesterol significantly. All this has to be studied further.

Mr. FOGARTY. What is safflower oil?

Dr. WRIGHT. Safflower oil is an unsaturated vegetable oil from the safflower. I do not know too much about safflower, except the safflower oil is the one that is most active of all of these in reducing cholesterol. It is high in terms of iodine content, which is one of the indications of this activity.

Mr. FOGARTY. I have heard of people supplementing or substituting peanut oil, and they claimed their cholesterol went down.

Dr. WRIGHT. I think the evidence is, if they really are strict with their diet and use the vegetable oil as a substitution, they may achieve this, but we believe that a very large proportion of patients will not continue to do that, but will think they can eat their usual high-fat diet and take an extra little drink of this unsaturated fat and do the same thing. This first experiment of ours, which, so far as we know, is the most carefully controlled one, done as a double-blind test of this particular type, has not substantiated that position.

Mr. FOGARTY. Have you ever used monichol. Do you know of that one?

Dr. WRIGHT. Yes. We have not found it has been helpful in our particular experience.

Mr. FOGARTY. I knew of a doctor who used to prescribe it, but other doctors told me they thought when a person lost weight that his cholesterol was down and he was just more careful when taking the monichol about watching what he ate. He lost weight as a result of what he had been giving up, and that was responsible rather than the monichol.

Dr. WRIGHT. What he gave up probably played a leading part in it. We should mention the important area of hormones. As we pointed out before, women are protected until their menopause, to a very large degree, from the development of atherosclerosis, and this must be due to hormonal differences between male and female. There is much evidence in favor of that. So, the obvious thing to do was to give males with a tendency toward coronary artery disease or abnormally high cholesterol female hormones. Unfortunately, this produced effects of feminizing the males and interfering with their libido and, therefore, it became rather unpopular and most of them would not continue it.

However, I believe that there is a tremendous opportunity for the fractionation of female sex hormones, attempting to fractionate out those components or fractions which are active in lowering and affecting the cholesterol back toward the youthful figures or the female figures without the feminizing influence.

There are a number of pharmaceutical houses interested in this to some degree but I think that this is an area where perhaps in the future the Heart Institute should consider using the contract system to really stimulate interest and have them produce a large series of these for clinical test.

Mr. FOGARTY. Do you think they are ready for a program like this?

Dr. WRIGHT. I think the particular group of substances and research in this field is definitely ready.

Mr. FOGARTY. It has been mentioned before by some that they did not think you were ready for any program like this yet.

Dr. WRIGHT. Like many of these things, at the time of developmental thinking, there will be those who will favor such a program and those who will think they are not ready for it.

Mr. FOGARTY. They have been working on a similar project at the Heart Institute out at Bethesda for 4 or 5 years and they have not made much progress, have they?

The hormones had these feminizing effects.

Dr. WRIGHT. They developed the feminizing effects. My point is I think we are ready now to stimulate great interest on the part of

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