On behalf of Dr. Clyde Yancy, Dr. Mandeep Mehra, and Dr. Rob Califf, and myself, Hector Ventura, welcome to this symposium. The program's title is ”Acute Decompensated Heart Failure: Charting a New Course.”

My job is to talk about the history. It is a great title. It is: ”A Glimpse of Yesterday: The Treatment of 'Dropsy.'”

So what is dropsy? It was called hydropsy or dropsy. It is a generalized swelling due to accumulation of excess water. And you can see a patient that you know quite well today, too. This is not a new thing. But that is the way heart failure was known: dropsy.

This quotation is from the daughter of the ruler of the Byzantine Empire, Alexius the First. This was one of the first descriptions of heart failure. His heart, they say, was inflamed. It was attracting all the superfluous matter, which will be all the cytokines. Every day he grew worse. He was unable to lie on either side. He was forced to sit upright to breathe at all. His stomach was very enlarged and his feet were also swelled up, and fever laid him low, some doctors wanted to do catheterization.

If by chance he did lie on his back, the suffocation was awful. Sleep would speedily overcome him. There was danger of asphyxia. Purgatives were not allowed. The doctors tried phlebotomy and made an incision in the elbow, and that also proved to be fruitless. Nonphysician, also, but very interesting quote. This is heart failure. Very good quote. And the fact is, you see the treatment. Phlebotomy.

Before I talk about the treatment, how about the concept? Because it is important to put the concept with the treatment.

This is from Dr. Arnie Katz. It was published in the Journal of Cardiac Failure. There are several paradigms used to understand heart failure. I do not want to repeat all of them, but you have clinical observations, obviously; then you have a correlation between anatomy and pathology and the clinical signs; then you have the hemodynamics.

We have here hemodynamics, you have now within the neurohormonal biophysics era, and then perhaps in the future. We are into the molecular biology paradigm.

A few months ago in September 2006, we published this paper in the Journal of Cardiac Failure. It is an Egyptian concept of heart failure. Look at this quote: “If you examine the obstruction in the abdomen, ascites, and you find that he is not in a condition to leap into the Nile, exercise intolerance, his stomach is swollen and chest is asthmatic, then you say to him, it is blood that got itself fixed and does not circulate.” That is heart failure.

Then what you do is to cause emptying by means of a medical remedy. Now, the medical remedy you see there is, one is almost digoxin, but you give him beer, which is a great diuretic, as you probably know. You can say cook in beer.

We published this paper after three reviews in the Journal of Cardiac Failure. You can see the authors: Maggie Saba, myself, Dr. Mehra, and Dr. Saleh, who is the curator of the Egyptian Museum in Cairo, believe it or not. I think one of the major ways people understood heart failure is when the circulation of the blood was defined.

This is a quote from William Harvey in his book, where he said that the heart was a pump. So not only that the blood circulates, it goes from the arteries to the veins and comes back to the heart, but the heart was the major reason why that happens. That is a change in paradigm because people felt before that the heart was a furnace to heat the blood.

Now, think about this. You have a pump, you put a cuff, and you measure pressures. Right? Okay. So this is the beginning of cardiology. For people that believe the GI doctors, or gastroenterology is the oldest subspecialty medicine, I have news for you: it is cardiology. 1628, right here.

Now, the other thing cardiology does, it measures. After Harvey, you can see the measuring of blood pressure.

This is from an Anglican priest, Stephen Hales, not a physician. He put a catheter and measured pressure. You can see it here.

Now, move on to 1831, then you have the concept of backward failure. Some people are older, as I am, they remember that concept. It is that the blood, the ventricle, hypertrophies and dilates, and then the blood stays back and causes edema. Congestive heart failure. This is James Hope from England.

More recently, or recently in the 1900s, early 1900s, James MacKenzie came up with the idea of the forward failure, which is the inability of the heart to maintain the circulation. The inability of the heart is due to the disturbance of normal adjustments of various factors concerned with the circulation. Perhaps he was talking about neurohormones. We do not know that.

If you put it together, in the early 1900s, 1914, people that went to school when I went to school, the only thing we learned was the Starling curve. It means the pre-load issue. When you increase the pressure in the veins, it is not associated with an increase in output in the ventricles, but a diminished output. So the more you fill the heart, the worse it gets.

Now, if you took it to the 1970s, Jay Cohn and others talked about this cycle of decompensation that you are familiar with when you are talking about systolic dysfunction. When you have systolic dysfunction, decreasing cardiac output, the hallmark of this heart failure problem, these mechanisms that are compensatory early on, long-term, are harmful. Then you have vasoconstriction, sodium and water retention, impedance, or increased peripheral resistance, the other hallmark, and more heart failure.

If you look at the paradigm in hemodynamics, that is the way it went from 1628 to 1970s.

So how do you treat this?

One famous technique was bloodletting.

This is bloodletting. I have to point out to you, if you can look at this, it says: "In short, bloodletting is a remedy if it is judiciously employed, it is hardly possible to estimate too highly." It works if you have heart failure. The problem is that they used it for headaches, stomach pain. But when you have heart failure, it works great. Some people might remember that. We do it today. This is a paper that we published with Dr. Mehra in the Journal of Cardiac Failure. We do the same procedure today, but it is called ultrafiltration. There are some more radical procedures.

This is the Asklepieion at Cos. This is from William Osler, about Asklepias. Dropsy was treated another way. Asklepias cut off the patient's head, holds him by the heels, lets the water run out and claps on the patient's head. It was done as an outpatient, no charge to anybody. And it was done with anesthesia. Great idea. It has to be a surgeon, by the way. Asklepias was a surgeon.

The Southey tubes: Another way to take fluid away. Look and see, you put these tubes in the legs. I remember this; but we did not have any other way to do it. You put the tubes into the legs, and you drain them. A patient came to my clinic 3 weeks ago, said, ”Doctor, do you have anything you can put in my legs?” I said, ”I do have some ... tubes.” This is from the New England Journal of Medicine, by the way, for people that read that journal.

How about digitalis?

This is the guy who discovered the properties of digitalis. This is William Withering, and his book is called An Account of the Foxglove. This is the first evidence-based book, nonrandomized, but evidence-based. It is 163 pages. If you give digoxin to everybody with ascites, the people who respond are people who have heart failure. Very good.

So he said, "On the contrary, if the pulse be feeble or intermittent, the countenance pale, the lips livid, the skin cold, the swollen belly soft and fluctuating, or the anasarcous limbs readily pitting under the pressure of the finger, we may expect the diuretic effects to follow in a kindly manner." Bingo! 300 years later, the National Institutes of Health (NIH) sponsored a trial that showed the same.

How about mercury? Paracelsus?

Mercury is a specific remedy for dropsy. That is what he said and it works.

John Blackall, MD The Nature and Cure of Dropsies. It is a very interesting book if you want to read it. He correlated the issues about urine, what type of urine do you need to give mercury? And it works. It was a urine with heart failure, people that have heart failure.

In a paper that we published many years ago, we looked at mercury. I would like to point out one thing about this. This is from William Stokes, of Stokes-Adams fame, who said, “I do not wish it to be believed that by mercury, we can cure dilatation of the heart; but many years' experience have convinced me that by the use of this remedy we can delay its production, (diuretics), remove the irregular (pulse), prolong the patient life, and again and again relieved him from dropsy." As by enchantment,” he calls, “remove the anasarca.” Very interesting. He used mercury as a diuretic.

Now, if you look further, then you have the mercurial diuretics. That's what they came from. And this came from Vienna.

This is Wenckebach and this is Alfred Vogl, an American student that was there. They gave novasurol to people who had syphilis and the nurse realized that people urinated more. Very interesting, right? So they give it to the patients that presented with anasarca. They noted that before the patient's death, he passed a lot of urine. Postmortem examination confirmed that the clinical diagnosis was not syphilis. This is a very important issue because it is the first time novasurol was used for the treatment of heart failure.

This is an original paper, a very landmark paper in the 1920s. This was published in the Middle European Journal of Medicine. Very good journal, by the way, if you want to read it. Many discoveries were published in that journal.

Now, these are the mercurial diuretics.

I have a few final slides. First paper, 34 patients. These are the questions to determine if the response was good or bad. Were the clinical signs of heart failure unchanged, improved, or worse? You have heard that before, right? Trials last week, this week. Did the need for parenteral mercurial therapy decrease? Did the need for hospitalization for cardiac reasons decrease? This is evidence-based. Was the oral diuretic well-tolerated and without any renal impairment? This is the 1950s.

And this is to show, you give an oral diuretic.

Look at what happened to the weight. Endpoint, weight. No difference.

How about diuretics? Well, sulfonamide, sulfas were discovered by this guy, Gerhard Domagk, who received the Nobel Prize.

Dr. Schwartz wrote a paper that was published in the New England Journal of Medicine, showing that if you give sulfonamides to people, they urinate more. Look at this. This is sodium. You give sulfonamides, look at this. Sodium in the urine, potassium in the urine increases. This was a study of three patients.

Karl Beyer, from Merck, Sharp & Dohme, synthesized something called chlorothiazide, something that we use today.

I am going to talk about the mechanisms of action of diuretics. You have the loop diuretics in the 1960s.

This is the first paper in 1969 showing that diuretics decrease cardiac output but also improve pulmonary pressure, pulmonary resistance and pulmonary vascular resistance, and increases total vascular resistance. People get better if you have heart failure.

This is another paper showing that if you give push, you have these issues about urine output. If you give continuous, it is much better. We are still doing it today, by the way. We do not know what we are doing, but we are doing it today.

And last, but not least, the point I wanted to make is you can see that when you have dropsy or heart failure. The story is you have to give them medicine to get people better. And that is exactly what it has been from 3,000 BC. The point is that this is the way it goes. You have a disease that is very bad, and you give a medicine, they get better. Can you imagine to first give mercurial diuretic and people get better? Amazing, isn't it?

I would like to show you a bit about nitroglycerin. We talked about digoxin, diuretics, loop diuretics, and now we discovered, by serendipity somebody gave sulfonamides, some people diuresed, and some people gave novasurol. It is amazing how medicine is, in a way.

So, here we have nitroglycerin; people love it. This was a study of 15 patients published in the New England Journal of Medicine, in 1957. The clinical and physiological data obtained after nitroglycerin administration under the tongue suggests that it has an important place in the management of patients with pulmonary hypertension, paroxysmal dyspnea associated with failure of the left ventricle. 1957.

In 1958, this was how people treated heart failure. I want to make a challenge to see how we treat it today. The rational therapeutic approach to the problem of congestive heart failure includes a three-fold exhibition of agents that increase cardiac output, digitalis; decrease venous pressure at rest, and ganglionic blocking agents; and decrease the abnormal retention of sodium, natriuretics or diuretic agents. At the end, all of these increase urine output. And this is the hemodynamic approach to the treatment of the disease.

I thought it was a good idea to give an introduction and try to go through the years how people treated this disease. Nothing had changed too much. Now you will hear the rest of the story: what we changed in the last few years.