EDDY BUCZYNSKI

In 1975, as a newly minted cardiologist fresh from Harvard's Peter Bent Brigham Hospital, I started into private solo practice in Worcester, Massachusetts. From my small office on the fourth floor of a relatively new medical office building, I could look directly across busy Belmont Street, Route 9, to the Memorial Hospital emergency department. As part of my staff appointment at Memorial, I was the director of the new coronary care unit. If I walked briskly, and traffic was not too heavy, I could make the journey from the office to the emergency room in roughly two and a half minutes, depending on the traffic coming down the hill. I consulted on a lot of patients with new onset or rapidly worsening (acute) heart failure for the ER team.

Heart failure (HF) is not a specific disease. HF is what medical doctors call a syndrome, a collection of various patient complaints (symptoms), evidence on physical examination (signs), and laboratory abnormalities (on blood tests, electrocardiogram, and imaging studies) that cluster together. The HF syndrome includes a broad spectrum of clinical problems that plague individuals who have impaired heart function. The heart is a pump; its mechanical functions are limited to filling and emptying. Nonetheless, a long list of specific diseases can cause impairment of either its filling, its emptying, or both. If and when the consequences of that reduced cardiac function come to dominate a patient's life, then he or she has the heart failure syndrome.

The 1970s and 1980s saw great progress in heart failure research. Laboratory and then clinical data established compelling evidence that the same physiological responses that are activated to retain salt and water under a variety of circumstances like dehydration, gastrointestinal fluid loss (vomiting or diarrhea), or bleeding are also highly activated in heart failure. Collectively, those responses are known as the renin-angiotensin-aldosterone system (RAAS). This occurs because the heart is not adequately filled or emptied, and the systemic arterial circulation is underfilled. The relative underfilling that occurs with heart failure stimulates the same RAAS responses that depletion of the circulating blood volume from dehydration or bleeding does. Think of it this way: it's as if you set your home thermostat on the living room wall to a comfortable seventy degrees. Then, when the house temperature was steady at seventy degrees, you take the thermostat off the wall and put it in the refrigerator (without cutting the wires!). Now the relocated thermostat gets a totally inappropriate input because it's cold in the fridge and will fire up the furnace to make the house hotter and hotter. The problem is identical with heart failure; the RAAS is inappropriately activated, like the thermostat in the refrigerator. Patients crave salt and water, and they retain both avidly, like the house getting hotter and hotter. Eventually, the patients become congested. They can't breathe comfortably because of congested lungs, and they gain weight from fluid retention in swollen (edematous) legs and ankles. In clinical trials, drugs that blocking the RAAS response (cutting the thermostat wires) produced important improvements in survival for long-term (chronic) heart failure patients.

On the other hand, acute heart failure remained a serious problem. A heart failure patient's clinical history is usually a variation on a theme, but every heart failure patient has his or her own individual story with memorable unique details. There is some underlying heart disease — high blood pressure or a previous heart attack. There's a week or two of feeling thirsty and not sleeping well, often in conjunction with some unusual personal stress — maybe a death in the family or a divorce. At first, the patient can't lie flat. He props himself up on two or three extra pillows, or he takes to sleeping in a chair or trying to catnap while sitting at the kitchen table. Then comes a particularly difficult night, the onset of acute heart failure. The patient wakes up short of breath, coughing. Some make it through the night and come to the emergency room in the morning. Some struggle on through the morning and try to take a nap after lunch only to realize that the symptoms are still there. Others don't come in until they get frightened when their sputum turns frothy and pink.

Eddy Buczynski's story was typical; it was also deeply personal for me. Eddy was the all-round manager of the building where I had my new office. He was a wonderful guy. Early on winter mornings, wrapped in his knit scarf, he made sure the plowing service cleared the parking lot, and then he opened a can of cat food for the neighborhood stray and let him chow down in the warm stairwell. He gave the older patients, particularly the ladies, a hand up the three short steps into the building. In the summer, he picked up any refuse that blew over from the convenience store across the street.

"Hi, Doc. You want the place to look professional, right?" he would say, smiling.

Eddy was five foot nine and about 225 pounds, balding, in his early sixties, with adult-onset diabetes and bad high blood pressure. After I had been there a few months, he showed up as a patient. His incredible affection for stuffed cabbage and kielbasa challenged his motivation, but we worked at keeping his problems under control.

Then, the following winter, Eddy's wife got sick. Very sick. After several years in remission, her breast cancer had returned with a vengeance. She was clearly going to die. Eddy paid no attention to himself or to taking his own medications; his life was limited to taking care of the building and taking care of his wife. After a few weeks of this, on a Monday morning, he stopped me on my way into the office, saying, "Doc, I gotta see ya today!"

We rode up together on the elevator. His shoes were untied, and he was sweaty. Sitting on the exam table, his blood pressure was high again, and he was short of breath. When he took a deep breath, I could hear crackles and wheezes at the bases of both lungs. His jugular veins were distended, and his ankles were swollen.

The acute heart failure patient literally starts to drown in his or her own bodily fluids. The heart's left ventricle can no longer support the circulation without an excessively high filling pressure. Because of the arrangement of the plumbing in normal adult human circulation, the back pressure from the failing ventricle is reflected as rising pressures in the lungs (the "pulmonary capillary wedge pressure"). Forced by the rising lung pressures, fluid seeps out of the vascular bed and into the air spaces (alveoli) of the lung. In Eddy's case, his diabetes was probably associated with asymptomatic coronary artery disease, and he had high blood pressure (hypertension) as well. Those were his underlying cardiovascular diseases. His shortness of breath and ankle swelling announced that he had developed overt heart failure.

"Eddy," I said, "you've got to come to the hospital. You've got heart failure."

"Doc, I can't. I just can't."

After about ten minutes of verbal head-banging, we agreed that Eddy would spend a few hours in the emergency room, where he got a couple of doses of intravenous Lasix and I renewed the prescriptions for his blood pressure meds.

In 1966, the US Food and Drug Administration (FDA) approval of furosemide (branded as Lasix), a potent, rapidly acting injectable diuretic and vasoactive drug, revolutionized the management of acute heart failure. Before Lasix, in an attempt to reduce pulmonary wedge pressure, heart failure patients were treated with morphine, mercurial diuretics, rotating tourniquets, and occasionally phlebotomy, and some also required sedation and artificial ventilation. Some died. The medical literature of the time did not include large studies, so accurately determining the mortality rate from those days is impossible. After 1966, heart failure could be managed acutely with oxygen, small doses of morphine, and intravenous doses of Lasix for diuresis. Diuretics act on the kidney to increase salt and water excretion. After the introduction of Lasix, 95 percent of heart failure patients survived the acute episode. Still, most of them were uncomfortable and short of breath for at least a day or two, and roughly half of them went home with lingering symptoms.

Eddy outlived his wife by about a year and a half; he spent his last six months on disability.

I maintained a private consulting practice in my Worcester office while holding a clinical faculty appointment at the University of Massachusetts Medical School for thirteen years. I cared for hundreds of patients with their own unique presentations of acute heart failure, their own variations of Eddy's story. In 1988, I left private practice to return to a full-time academic position. By the mid-1990s, I was a midcareer academic cardiologist on the faculty of the University of Florida, and Lasix was a thirty-year-old drug. Nothing had changed for patients with acute heart failure.

When I had the opportunity to participate in pharmaceutical clinical research that would help develop a new drug for acute heart failure called nesiritide (eventually brand named Natrecor), I was more than ready.

FROM THE DOG LAB TO MOLECULAR STRUCTURE

The chain of scientific discovery leading to nesiritide had begun decades before I reached Florida. The best place to start is in the mid-1950s at a laboratory on the Wright-Patterson Air Force Base in Dayton, Ohio. A veterinary surgeon, Captain J. L. Reeves, had joined Drs. J. P Henry and J. W. Pearce to lend his skills to their research efforts. In the lab, gowned and gloved, Reeves neatly opened the chest of an anaesthetized dog that was lying in a surgical cradle with a breathing tube and a bladder catheter in place. Without interrupting the flow of blood through the lungs, he gradually expanded a balloon in the holding chamber for the right heart (the right atrium). The expanding balloon simulated the effect of blood volume expansion on the heart by mechanically stretching the atrium without actually giving the dog additional blood or fluid. The catheter in the dog's bladder soon started to fill with urine.

The experiment showed that stretching the right-sided holding chamber of a dog's heart with a balloon made the dog pass more urine (Henry and Pearce 1956). The inescapable conclusion was that by some as-yet-unknown mechanism, the heart had sent a signal to the kidneys. How?

As with most stories, this starting point is arbitrary. Henry and Pearce were looking for something with their experiments. What was it, and why were they searching?

By 1950, many of the questions about the structure of the body had been answered. Anatomy, except for the description of subcellular structures like the tiny energy-generating structures inside the cell called mitochondria, had largely solidified into a fixed body of knowledge. In biochemistry, the basic processes were also largely understood. Although for biochemistry, new breakthroughs — particularly the dramatic discovery of the structure of DNA — were still ahead. For researchers in physiology, the biomedical discipline that deals with the engineering questions of "how does it work?" the body remained full of terra incognita to explore. One of the critical physiologic questions that had started to yield preliminary answers was, "How do animals, particularly dry-land animals like us, regulate the salt and water balance of our fluids to maintain the chemistry of our interior environment constant at levels fairly similar to seawater?"

Some hints to the answer had come from the observation that when a disease like tuberculosis destroys the adrenal glands (the small, fleshy organs that sit just above the kidneys), patients easily lose excessive amounts of salt and water. Their inability to retain salt and water leaves them vulnerable to perilously low blood pressure following minor insults, like gastroenteritis, that healthy individuals tolerate relatively well. Clinically, the condition is called is called Addisonian crisis. Early on, the adrenal glands were recognized as an essential part of the critical regulatory pathway that stimulates salt and water retention.

As the details were worked out through multiple experiments, the regulatory pathway became well known as the RAAS, which is so important in heart failure. It acts as a powerful accelerator to increase heart rate, drive salt and water retention, and raise blood pressure. But physiologists had come to understand that there must be a counterregulatory mechanism in order to balance the RAAS. There had to be a brake that could cause reduction in blood pressure and encourage salt and water excretion. Physiology regulates processes with both positive and negative controls, just as the driver of a car has to use both the accelerator and the brake to control the vehicle's speed.

That day in 1950, Henry, Pearce, and Reeves knew at least the approximate location of the accelerator; they wanted to learn more about the brakes. The results of their experiment showed that the heart could signal changes in its volume to the kidney; they had the first big link in what would grow to become a chain of evidence.

Fast-forwarding to 1983, and with a change in venue from Dayton, Ohio, to Canada, the next critical link would come from Adolfo de Bold's physiology laboratory at Queen's University in Kingston, Ontario. De Bold, a brilliant Argentine émigré, had developed a technique to study the function of an isolated perfused rat kidney. As he described it, "The kidney rested in a water-jacketed kidney holder and the perfusate was kept at 37.5°C and oxygenated with 95% O2 - 5% C02" (Baines, de Bold, and Sonnenberg 1983). In other words, this preparation totally isolated the kidney, keeping it alive but independent from the rest of the body.

Based on the experiments in Dayton and additional later work, de Bold had worked out a technique to homogenize rat heart atrial tissue. He had then partially purified the homogenized material. When he injected the partially purified substance — whatever it was — intravenously into rats, it consistently caused changes in the composition of their urine.

Did the unidentified substance in the homogenized tissue act directly on the kidney? Did something in his tissue preparation carry the message that Henry and Pearce had shown that the heart sent to the kidney? De Bold wanted to know.

With his isolated perfused kidney, he could duplicate the effects of the expanded balloon with the atrial tissue extract. He was closing in on a signal that counteracted salt and water retention. He injected increasing doses of the partially purified material into the fluid perfusing the kidney. As he did, the isolated kidney produced urine with increasing amounts of salt and water in response.

In his words, "In conclusion it appears that AE [atrial extract] is a potent natriuretic, chloruretic, phosphaturic, and diuretic in isolated perfused kidneys. Its action does not involve alterations in catecholamine excretion" (Baines, de Bold, and Sonnenberg 1983).

So far, the science showed that the atrial muscle cells of the heart contained a chemical messenger. When the cells of the atria were stretched by a balloon or by expansion of the circulating blood volume, they released that messenger into the bloodstream. The messenger, whatever it was, caused blood vessels to dilate. However, de Bold, with his isolated kidney preparation, had proved that independent of the blood vessel effects, the messenger substance also directly increased salt and water excretion by the isolated kidney. In physiologic terms, the messenger was a salt excretion (natriuretic) hormone. The outlines of the regulatory system were growing much clearer.

Just two years later, de Bold (de Bold 1985) described purified atrial natriuretic factor, or A-type natriuretic peptide (ANP) as we now call it.