Stevo Julius

Quotes

[I] had to extract myself again from Croatia and came here in ’64. At that time there was an interesting development in hypertension that everybody was almost “sure” that the role of the autonomic nervous system really is minimal. And that had to do with a number of things.

Number one, it had to do with the fact that after autonomic blockade there is still increased vascular resistance. So people thought there must be something vascular, forgetting that they were studying late phases of hypertension where, indeed, there were vascular changes. The other thing that was quite clear was that you cannot generate a good animal model of neurogenic hypertension.

In the meantime if you played with the renal artery and the kidneys and so on, you could create hypertension (Goldblatt).

Third, is that one could create some sort of hypertension with central stimulation but when you stopped stimulating it went away.

And then finally, Guyton in his system analysis computed that the nervous system has very little “gain” as he called it. On the other hand, I knew in fact of Fejfar and Widimski’s work on the high cardiac output state, which was associated with tachycardia and mild hypertension. And having the idea that there must be something to this idea of autonomic function, I started to work in this area. (4)

Very soon it was clear that the evidence for what we called the hyperkinetic state is quite overwhelming. By the time I collected my own series, which was in about ’69, there were already at least 15 references, solid papers all over the world picking up on the Czechs’ work that showed a state of tachycardia with increased sympathetic drive.

But two issues remained. One was whether this is some weird sub-form of very mild hypertension and whether that has anything to do with future severe hypertension. And the other issue then was if this is so, and it is a subset, what characterized those involved and why is the actual heart rate and cardiac output elevated? That was not truly known. There was some early work that suggested these people had increased norepinephrine levels in the urine. (5)

For a while we had a little group that would meet who were interested. Then I was lucky to run into Jim Conway. Jim Conway was a great scientist who came to work with Sydney Hoobler and worked with me and who was an organic-minded investigator who was tremendous in methodology, who studied hemodynamics and who kind of corrected, what I would say, my views of science. Everybody that comes from the east (of Europe) is basically doing little research while fantasizing a lot.

And he put me to the hard task to prove my ideas. And the first serious work we did was autonomic blockade of the heart in which we gave intravenous propranolol and atropine. And we could show that the elevation of the heart rate and cardiac output disappears after these blockades. So it was clearly shown that this is neurogenic. It also meant that these people didn’t inherit some unusual pacemaker or something like that. And also, incidentally, it differentiated this group from what was then described by Ed Froelich as hypersensitivity syndrome. (6)

So that you could now define a phenotype that clearly had neurogenic hypertension…The side story in all of this is as we were doing this cardiac blockade we also described that vagal tone, parasympathetic tone is decreased. So you had an increased sympathetic, decreased parasympathetic tone… the term drive is more appropriate than tone, actually….We used it only for proof that this is integrated centrally. It must be coming out of the brain because in the medulla oblongata you have integration of the vagus and sympathetic tone. So we were doing that work and then it was quite clear that we had come to the end of what we could do in the laboratory… and the real issue became whether this condition that we see – you will understand this as an epidemiologist – this is a highly selected group of scared people or for that matter it could be that our normal subjects were particularly phlegmatic. And it was not clear whether that condition can be found in the general unselected population. Most of the studies that have described this syndrome have come from laboratories like ours. And we decided to try and look into what we could find in an epidemiologic study. (10)

I worked in the Tecumseh Study as a data collector and understood the tremendous meaning of these fantastic things that Dr. Epstein and others developed. But I wasn’t ready to go into the field until we had appropriate methods to measure cardiac output through hemodynamics… And eventually the echo Doppler method came in in which you could measure both the echocardiographic, but more important, the Doppler flow through the aorta and with echocardiography you could determine the size of aorta and then you could assume what the cross-sectional area was and then calculate the cardiac output. And that was a very reliable method and so we were then ready to go into the field at Tecumseh. (12)

And then another fellow in my laboratory, Dr. Brant Egan, who was interested in vascular resistance and alpha adrenergics, constantly kept telling me that the most important thing in this field is the fact that these people are overweight always. I looked at the overweight just as a nuisance because it was a nuisance in comparison with other people – how to normalize it and so on. And he was starting to be very interested in insulin, when at that time it became known that there is an insulin resistant state.

Brant did leave us, but he said, “You know when you go to Tecumseh and start doing your own research, you should focus on… insulin.” And I actually did it more or less because he said so, without much understanding it. Then, of course, it became a major finding and new idea.

So we went into the field and, in short, we could find what we found in the laboratory. We could find it in unselected people from the general population who did not know that they had high blood pressure. We just measured pressure and found it elevated… So what we found was elevated plasma norepinephrine being elevated in the hyperkinetic state, in the high cardiac output state which we measured. We found evidence of increased hematocrit. All of that. But then in addition to that, it was very clear that they had already the beginning of the so-called metabolic syndrome. They were overweight, they had high insulin levels, abnormal insulin to glucose ratio, and all the characteristics of what we would now call metabolic syndrome. (14)

A Unified Field Theory?

So now the issue became how does this all tie together? It’s there, it seems to be real, it’s not only blood pressure, there are a number of other abnormalities including the metabolic syndrome – high hematocit, increased tone, all of those. And, of course, I always believed the nervous system… could theoretically explain all these phenomena based on… increased vascular tone.

But insulin was a more difficult issue and so was overweight. I then looked at the literature and…There was a number of very interesting papers from Sweden that dealt with vascular biopsies and showing capillary rarifaction …. less open capillaries in skeletal muscle. There was evidence then of decreased capillarity in the skeletal muscle and the thought came that maybe what was happening is that there is a decreased delivery of insulin and glucose to skeletal muscle and that, therefore, a hemodynamic component to insulin resistance. In other words, because of the vascular spasm it is conceivable that you deliver less nutritional flow to the skeletal muscle. I worked on that [I thought] quite alone…I thought maybe the sympathetic nervous system causes insulin resistance by causing vasoconstriction in the skeletal muscle and thereby decreasing glucose utilization… So he had done these experiments and sure enough, when he caused vasoconstriction with this, glucose utilization in the forearm decreased. So this did show the feasibility of the whole concept… So, at least we got as far as saying the sympathetic nervous system certainly is responsible for blood pressure in about 30% of patients – males chiefly. It is also very likely responsible for the high hematocrit. It may well be responsible for the insulin resistant state. Certainly could be responsible for high blood pressure because sympathetic drive increases. [ed. Almost a unified field theory you have now.] (15)

At that time the overweight still remained and remains today a real issue. The chicken-egg issue. Is this all really because people overeat and then release more insulin and then insulin works on the brain and increases sympathetic tone and then leptin also comes in. That concept has been proposed by Lowell Ansburg that there is a primary eating disorder and then you kick in your sympathetic tone in order to get back into a calorie balance because the sympathetic tone, which as you know, increases basal metabolic rate and also is involved in thermogenic responses to food. And that is a concept that is correct for those people. But we were also aware that there are some people who have everything else the same and yet are not overweight. Still have this increase in sympathetic drive and also in insulin. (18)

A Bad Word: Salt

I think there is no doubt in my mind that the sodium balance is very important – sodium/potassium ratio – is very important and epidemiologic studies are confirmatory. I think you have the same problem that I have and still have that the sodium people are lumpers, just as I was. And to me it’s clear that there must be a subset of sodium sensitive people. Myron Weinberger has done a lot of work on that. The problem with this is that it’s very hard to define the sodium-sensitive individuals. The best way to define them now is the way you wouldn’t want to do it. And that is you don’t find them responding to sodium with an increase of blood pressure. You find them responding to low sodium intake with a decrease of blood pressure… they are probably already at their maximum sensitivity. So when you give more sodium nothing happens.

I think it is an issue of phenotyping. There is a guy who spent a lot of work and is not well known, but he is an excellent man…and has done a lot of work on genotyping and phenotyping and measuring properly with ambulatory blood pressure monitoring. He can show that sodium intake does actually increase pressure two or three millimeters and that is good enough. So he has done, probably, the best work in that area. (29)

The Thrifty Gene Hypothesis

We cooperated with Jim [Neil] on an intellectual level mainly many years. He’s a great guy. He’s very impressive. …I learned from him this thrifty gene hypothesis and so on. Later he revisited that issue, and I’m co-author on that paper, whether there is really evidence of [a] metabolic syndrome. And on statistical grounds, it was very difficult to show that this is a separate syndrome. It was a complex statistical model. I personally, because I’m convinced of the cogency of the argument of increasing sympathetic tone, that there is a syndrome somewhere there. But it was not possible to show it with statistical analysis. I take statistics with a grain of salt and I don’t understand it too well. But Jim was a great thinker. He was a fascinating man. (34)