Heart failure clairvoyant reviews his decade-old predictions and looks to the future

Shelley Wood

June 26, 2001

Katz and dog: Dr Arnold Katz, and his springer spaniel Max (Source: Arnold Katz)

Norwich, VT - Before getting down to the business of talking about heart failure (HF) with theheart.org, Dr Arnold Katz takes a moment to switch phones so he can settle into a comfortable chair where his springer spaniel can join him. For almost half a century, Katz has been thinking, reading, writing, teaching, or expounding about HF. Now at the age of 68, still teaching, but no longer seeing patients or conducting his own research, little has changed. He has a dog on his lap, but he still has his sage opinions.

Starting with dogs. "The modern treatment of most heart disease, includes neurohumoral blockade," Katz explains. "And what these drugs do is the same thing that happens when you pet a dog, that is, it stops all those evil humors from coming out of the autonomic nervous system. I view a dog as a sort of like a lightening rod, you touch it and all of the angst flows out through your fingers and into the dog and goes harmlessly into the ground. Owning a dog is like a cheap form of blockade."

Katz and his opinions

 

Ten years ago Katz, then a professor of medicine at the University of Connecticut, was asked to forecast the future of HF management in 2001 for an industry-sponsored supplement appearing in the American Journal of Cardiology. At the time, he prophesized that the major strides in this field would be made on the basis of a "paradigm shift" in how the disease and its treatment were regarded. Now, in an article appearing in the June 15, 2001 issue of the American Journal of Cardiology, Katz looks back at the past decade, reviews his predictions, and in a special interview with theheart.org, peers again into his crystal ball to see what the future holds.

Katz doesn't sign his name to his theories about dogs, no more than he will take the credit for the radical re-thinking among cardiologists in the early 1990s regarding the underlying causes of HF. This resulted from an accumulation of a great deal of new knowledge, both in the basic sciences and from long-term clinical trials, he says.

 
Before 1990, heart failure was viewed largely as a hemodynamic disorder. That's still true, but the new paradigm is that a major underlying problem in heart failure is its progression.
 

Until about a decade ago, says Katz, the primary goal in treating HF was to alleviate signs and symptoms and attempt to modify the abnormal circulation and its effects on the body.

"Before 1990, heart failure was viewed largely as a hemodynamic disorder," Katz told theheart.org. "That's still true, but the new paradigm is that a major underlying problem in heart failure is its progression, and I think that has become very clear over the last 10 years."

This progression, and its basis in complex molecular changes taking place in the heart, is a concept that first began to occur to Katz in the mid-1980s ahead of many of his peers, gaining broader acceptance in the early 1990's. "Most people didn't pick up right away on how important progression really was," he says simply. Times have changed.

The tools of molecular biology

Key to Katz's predictions both for 2001 and beyond is the idea that the progressive changes which take place in the heart, resulting in end-stage HF, occur at a molecular level triggered by, or in tandem with, physiological changes.

"What we have now, is an appreciation that one of the major problems in heart failure is the progression, which seems to be due largely to molecular abnormalities developing in the heart muscle that shorten life expectancy," Katz explains.

He predicts that over the next decade and thereafter, advances in HF will not involve another major paradigm shift. Rather, research will delve further into "recently established directions, where the tools of molecular biology will identify new ways to inhibit progressive dilation (remodeling) and slow deterioration of the failing heart."

This can't be true!

To date, all of the agents that appear to inhibit remodeling function at the neurohormonal level by blocking proliferative signaling Katz explained to theheart.org. These include ACE-inhibitors, beta-blockers, and to a lesser extent, spironolactone. Ironically, all three types of drugs were first tried in HF patients for purposes other than inhibition of proliferative signaling.

Survival benefit with ACE inhibitors in CONSENSUS (N Engl J Med 1987; 316:1429)

 

Katz remembers "vividly" the response in the mid 1980s, when the CONSENSUS I trial, showing a 50% prolongation of survival in heart failure patients taking enalapril, was first presented. "People began to jump up and down and say, this can't be true, other vasodilators don't do this. It occurred to me, listening to that presentation that maybe there is more to ACE inhibitors than vasodilation."

Now, with an evolving appreciation of the multiple actions of these drugs, physicians are better able to understand how they interfere with molecular processes taking place in the failing heart. "What offers real hope and promise for the future are data from the ACE inhibitor and -blocker trials which show that both of these drugs can inhibit and, for a time in the average patient, reverse the maladaptive growth process called remodeling."

Finding and blocking other pathways

The aim of future research, says Katz, will not be so much to find newer or better -blockers and ACE inhibitors for heart failure, but to "find out more about what exactly is going on to destroy the heart, and how to slow or reverse these processes."

Moreover, Katz observes, both -blockers and ACE inhibitors act on different molecular pathways, and the process of maladaptive growth in the failing heart is likely the result of multiple, complex, proliferative signaling pathways that could potentially be independently inhibited by different drugs. "This, like so many other fields, is an area where we're going to need multiple drugs," Katz predicts.

Katz points out that endothelin antagonists, "are yet another class of drugs that have the potential to be additive to everything else, because endothelin, which is a vasoconstrictor, is also a very powerful proliferative signaler." So far, he adds, mixed trial results make it difficult to predict whether endothelin blockers will yield an overall benefit. "At least in theory there's something to be gained from these drugs. But you never know until you test them in long-term clinical studies, and then there's always so many surprises."

Looking further down the signaling cascade
A signal transduction cascade showing the 'flow' of processes that allow sympathetic stimulation to increase contractility

 

Katz also predicts that future drug studies will attempt to block the molecular changes taking place in the heart, not at the beginning of the signaling process, where extracellular messengers bind to membrane receptors, but at a point further into the sequence of intracellular signaling events. He likens the process to a waterway in which a major river branches off into a series of smaller streams. "All of the drugs that we now have are at the beginning of the river, at the top of the signaling cascade, stopping the whole process from the top. And where I think people are beginning to look is further down this cascade, where one can achieve more selective responses."

Being more selective

Katz gives the example of -blockers that inhibit all of the responses that -agonists initiate, some of which might actually be beneficial. "Do you need to block all the effects of -agonists to get the anti-proliferative effect? Wouldn't it be nice if one could get into the cell and find the signaling system that is causing cells to elongate, which is probably one of the major causes of remodeling?"

Likewise, Katz muses, although early results from studies of the TNF inhibitor etanercept have proved disappointing in the treatment of HF, the poor results may indicate that the agent being tested may have been too broad in its molecular impact.

"TNF alpha has more effects than you can shake a stick at," says Katz. "It has some beneficial effects as well as some harmful effects. And what you'd like to do is block the harmful effects of cytokines, which are plentiful and very well known, and leave intact the beneficial effects."

"If one had a better drug, a more selective drug . . . then you'd be miles ahead."

Endpoints for today and tomorrow

One of the major changes since the 1980s is the shift in clinical trial endpoints away from measurements of exercise capacity, hemodynamics, or quality of life, says Katz. "Those endpoints have turned out to not be very useful and in many cases quite misleading in terms of long term prognosis."

Major HF trials today are looking more at survival benefit, freedom from hospitalization, and change in functional class. Katz says, "My guess is the endpoints are not going to change, although we may add some, such as 'reverse remodeling.'" He makes the tentative prediction that the next 10 years may bring about some reliable surrogate endpoints for evaluating the effects of different agents on heart function.

"Are there other things you can look at without having to run a $40 million trial?" Katz queries. "It may be that we will begin to find some good surrogate endpoints, such as reduction in left ventricular mass, so that you can get some answers without having to spend so much money and wait so long, by which time the question has lost some of its luster."

Maladaptive cardiac hypertrophy: Concentric and eccentric hypertrophy, compared to a normal heart. Adapted from Katz, Physiology of the Heart (3rd ed), 2001

 

What is needed, Katz muses, is a surrogate marker of maladaptive cardiac hypertrophy. "The trouble with growth is if you're going to look at heart muscle you've got to look at heart muscle, and heart muscle doesn't float around in the blood stream. So is there going to be something that you can look at in a lymphocyte? Or in a buccal-mucosal cell? I don't know. That's too blue-sky for me."

Complex interactions

Equally up in the air for Katz is the issue of how the ever more complex research being conducted by scientists and pharmacologists will be understood by physicians and cardiologists and translated into clinical practice. Recent controversies in the arena of race-based therapy for HF, stand as a case in point.

"There is nobody that would say that skin pigmentation has any influence on your response to therapy," states Katz. "But clearly there are certain genes that segregate with skin pigmentation, so people who are coming from one region of the world will have a different set of genes than people who come from another region of the world. And these genes in many systems including the heart, can reasonably be expected to affect the response to therapy.

The more troubling question, says Katz, is how the bulk of physicians will ever be able to understand the complex interplay between different drugs, and between drugs and the individual genetics of any given patient. "I grew up in a much simpler era when you could go from the bench to the bedside to the laboratory to the class room and it sort of hung one piece on the other. It's all splayed apart now," he laments. "How is anybody going to be able to treat patients when you have to use combinations of 4, 5, 6 and maybe even more different drugs that can slow the progression in heart failure. How do you use them?"

The "solution," Katz insists, is to have "a real understanding of the mechanisms of disease as they are manifest in the individual patient, the mechanism of drug action as they occur in the individual patient, and the interplay between mechanisms of disease and mechanisms of drug action. This, unfortunately, is made difficult by reduced time for the teaching of basic biomedical science in the medical curriculum."

Emperor's new clothes?

If Katz is an enthusiastic spokesperson for the benefits of HF research, he is even more passionate about the future of medicine more broadly, and particularly the importance of medical education. In this area specifically, Katz harbors some anxiety about the ability of tomorrow's physicians to truly comprehend the mechanisms of both disease progression and drug action in HF.

"You can't emphasize humanistic teaching enough. The trouble is, you cannot afford to de-emphasize the science."

"I view some of the current trends in medical education as like purchasing a set of the Emperor's new clothes," Katz told theheart.org. "To move away from teaching the core basic sciences that serve as the foundation of patient care, to focus instead on teaching students how to 'love your patient' will put the next generation of physicians at a disadvantage. They will lack understanding of, and so the ability to utilize optimally, the vast amount of new information now coming from molecular biology."

According to Katz, "humanistic medicine," that is, the compassion and attentiveness of a good doctor, is essential. "You can't emphasize humanistic teaching enough," he insists. "The trouble is, you cannot afford to de-emphasize the science. It's not that we're teaching too much about humanistic medicine, its that we're taking away from teaching science. . . And I'm not sure that you can learn humanistic medicine in the classroom. The way you learn how to take care of patients is by taking care of patients under the guidance of an informed and caring clinician."

"My bon mot is that although medicine is now about 20% science and 80% art, woe unto the patient who receives only the art without the science - or with only mediocre science."

No easy solutions

As medical research delves more deeply and intricately into molecular biology and human genetics the gaps yawn wider. There are no easy solutions, Katz admits, although he ventures that medical education may have to be a longer process. He also hypothesizes that the current emphasis on generalists, on primary care, may not be appropriate. "It may be that what is needed most are people who are able to deal with the molecular abnormalities responsible for disease." Finally, he insists, "therapy has to be tailored to the individual. The 'one-size-fits-all' method really doesn't work. And you really need people who know how to match therapy to the needs of the individual patient."

Katz himself spent more than 40 years moving between the bench and the bedside, teaching the while, before stepping down from his position as Chief of Cardiology at the University of Connecticut in 1995 and relinquishing his clinical and laboratory duties at the same time. But he still teaches and writes. In addition to lecturing as a professor emeritus at U Conn, he also teaches at Dartmouth College as a volunteer, receiving in return "a place to park, library privileges, and above all, contact with students and participation in the academic program, which I love."

One month away from his 69th birthday, he has no intention of giving it up. "Not until I fall into my cups," he quips. "If I were to stop teaching my mind would go dead."

Taking stock of 1991's predictions

Katz's paper in the June 15, 2001 issue of the American Journal of Cardiology takes stock of his major predictions of 1991, some prescient, some not. He takes a certain pride in his early prediction that -blockers would become "first-line therapy" for HF. "That's one that most people did not see coming," he told heart wire .

Katz writes that in 1991, he "saw little hope for efforts to increase energy production in the failing heart" through new types of vasodilators, substrates or metabolic regulators. Now in 2001 he writes, "this prediction, unfortunately, has not been disproved."

Where Katz acknowledges he missed the mark was in predicting that there would be no major advances in the field of diuretics. What he did not foresee was the rise of spironolactone, which in addition to blocking proliferative signaling is also a potassium-sparing diuretic.

Katz also admits that he "really missed" when he predicted that by 2001 physicians would be using agents that promoted relaxation in the failing myocardium. "That has sort of faded away into the background," Katz declares. "Relaxation abnormalities are probably turning out to be less important and less subject to modification with therapy than I would have predicted in 1991."

-SW

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