Arterial Inflammation

Thursday October 7, 1999

THE WALL STREET JOURNAL

Heart-Disease Sleuths Identify Prime Suspect: Inflammation of Artery.

The Body's Efforts to Repair Irritated Lining of Vessel Can Backfire Disastrously Plaques Burst Like Popcorn

By RON WINSLOW

The mechanism of most heart attacks, in the popular view, is pretty clear. A coronary artery is gradually narrowed by a buildup of crud as in a corroded pipe, until finally, when the artery is, say, 80% closed, a small clot gets stuck in it and shuts off blood flow to the heart. The more the artery is narrowed, the greater the risk from a clot.

But the popular view is wrong.

In fact, about 70% of heart attacks are caused by much smaller obstructions, which narrow the artery by perhaps only a third or so -- too small to cause symptoms or to be detected by an X-ray angiogram. This is one reason for a dismayingly common phenomenon: Someone comes out of a heart checkup with a clean bill of health, and soon afterward has a severe or fatal heart attack.

Now, in a flurry of new discoveries, some just emerging from academic and corporate laboratories, researchers are beginning to explain why this happens. In the process, they are unlocking secrets about the biological forces that ravage the coronary arteries and producing new insights that could eventually transform treatment of the West's deadliest disease.

"Our entire understanding of what causes coronary atherosclerosis is changing right before our eyes," says Paul Ridker at Harvard Medical School.

Going Pop

The hypotheses from these scientists are startling, and none more so than this: The body's defense system -- there to protect it from harm -- is a key culprit in heart attacks. It can cause small arterial deposits to suddenly rupture like popcorn kernels, choking off the blood supply to the heart.

How this could be so involves a concept that is at the center of the new research: inflammation. Researchers believe that coronary-artery disease is an inflammatory process, characterized by a decades-long cycle of irritation, injury, healing and reinjury to the inside of the blood vessels.

Under certain circumstances, "the body's defense mechanism turns into a betrayal," says Valentin Fuster, director of cardiovascular research at Mount Sinai School of Medicine in New York.

Not Just Sludge

These notions have propelled research into the biology of atherosclerosis, as heart scientists try to understand what makes plaques rupture and find ways to identify and treat them before they do. It "isn't just sludge caking up on the vessel wall," says Peter Libby, chief of cardiovascular medicine at Harvard Medical School and Brigham and Women's Hospital. "There is an inflammatory response," he says, that "alters the biology of the artery wall and can make the plaque susceptible to rupture."

The new research doesn't detract from well-known risk factors. On the contrary, it bolsters arguments for controlling blood pressure and cholesterol, avoiding smoking and adopting a healthier lifestyle. But the inflammation thesis is opening up tantalizing new approaches to prevention and targets for treatment.

More approaches would certainly be welcome. For all the progress that has been made, heart disease kills nearly a million Americans every year, far more than any other disease. About 1.5 million suffer heart attacks. Bypass surgery and artery-opening technology such as angioplasty balloons and stents -- anchors of a $200 billion industry to treat heart disease -- are very effective in relieving its chief symptom, the severe chest pain called angina. But they do almost nothing to arrest the disease itself.

Puzzles Remain

In the past decade, cholesterol-lowering drugs called statins have emerged as a powerful weapon, with proven ability to prevent heart attacks, reduce the need for bypass surgery and angioplasty, and save lives. But statins don't save everyone. And in terms of knowing who is most at risk, a cholesterol test, though a strong predictor, is far from perfect: Half of the people who suffer heart attacks have "normal" cholesterol. In fact, up to one-third don't seem to have any of the accepted risk factors.

The new research could help. Dr. Ridker's work, for instance, suggests that a test for signs of inflammation, if added to routine cholesterol screenings, would greatly improve doctors' ability to detect heart disease well before it reaches harmful advanced stages.

To be sure, it's a long way from insight to proven hypothesis in medicine. And while inflammation is the hot topic in cardiology, what it means is the subject of contentious debate. One key question: Does the presence of inflammation truly point to new treatment targets, or just reflect the effects of such already-known risks as high cholesterol and smoking?

Some researchers wonder if more benefit might be gained by investigating causes of the arterial injury rather than the body's response. In addition to cholesterol, smoking and high blood pressure, potential culprits include certain bacteria, viruses and high levels of a protein constituent called homocysteine.

But the inflammation hypothesis is gaining influential converts. The pharmaceutical industry is hunting for agents that might attack key steps in the body's inflammatory response to artery irritation. And in just the past few months, doctors at the renowned Cleveland Clinic have begun checking some heart patients more aggressively for markers of inflammation that may indicate heightened risk of more trouble.

Those most prominent in making the case for inflammation include teams led by Harvard's Dr. Libby, Mount Sinai's Dr. Fuster, and Russell Ross, a researcher at the University of Washington in Seattle, who was a longtime champion of the concept until his death early this year.

Early Start

The picture that emerges from their labs as well as others is of a disease that begins as early as adolescence with an initial irritation to the artery's inner wall, called the endothelium. This sets off alarms summoning the immune system and the broader inflammatory response, dispatching cellular soldiers to fight the invaders and fix the damage.

If the injury is a one-time event, this is no problem. The immune-system players retreat, and the inflammatory response that accompanied their efforts recedes as well. But over decades, with persistent irritation such as from high blood cholesterol or exposure to cigarette smoke, this becomes chronic, and the body's repair machinery begins to run amok.

"It's a smoldering process," says Dr. Libby. As it proceeds, "the normal defense mechanisms get turned against you." For instance, an irritated cell in the lining produces molecules that act like flypaper to attract the beneficial repair crews. But over time, these stuck molecules become the seedbed for eventual cholesterol deposits called plaques.

Most plaques grow slowly, probably through a helter-skelter series of small fissures that rupture and heal over again and again. They amount to scar tissue on the artery wall. And they house pools of cholesterol, which become covered by a fibrous cap.

Eventually, as these plaques mature, they may fill 70% or more of the blood vessel. Obstructions this extensive are readily detected on an angiogram, and the restricted blood flow may cause angina. But these plaques typically stabilize and pose little risk of a major rupture.

The Dangerous Ones

By contrast, younger plaques are soft, covered by a thinner fibrous cap and contain a particularly rich lode of cholesterol, making them volatile. They may narrow the artery by only 30% or 40%, and cause no symptoms. Because the vessel wall often accommodates them by expanding outward, they also may go unnoticed on an angiogram.

If they rupture, however, they trigger massive, sudden clots that can fill up the entire artery and cause a life-threatening heart attack. For patients, says Dr. Ridker, the issue boils down to this: "Everyone has atherosclerosis. The question is, do you have an unstable plaque?"

Here, inflammation comes in again. One function of the body's repair system is to clear cholesterol from the cells lining the artery wall, a role that falls to cellular garbage trucks called macrophages. They swoop in and suck up the cholesterol from the plaque and haul it away.

But in a particularly fatty plaque, the immune-system macrophages can become engorged with so much cholesterol that they can't do their job. They turn into what scientists call foam cells -- because they become so laden with fat they are squishy.

Unable to perform their duties, they die. As they die, they add their contents to the cauldron of plaque bubbling under the fibrous cap. And they release toxic substances that lay the groundwork for the plaque to rupture.

Eroding the Structure

One of the toxic culprits they release, identified by Dr. Libby and his colleagues, is a group of enzymes that attack the fibrous cap covering the plaque, chewing up structural components and destabilizing it. That appears to make it vulnerable to some other event -- like a stressful argument or strenuous snow-shoveling -- that raises blood pressure and causes the plaque to break open, spilling its clot-causing contents into the blood stream.

At Mount Sinai, Dr. Fuster and his colleagues found that macrophages can do even more damage. It turns out that they release another toxic substance in their death throes, called tissue factor, which increases the tendency of blood to clot.

He teamed up with Juan Jose Badimon, another scientist in his lab, who invented a chamber that mimics conditions in which blood flows through diseased arteries. When they used it to expose blood to plaque specimens that were rich in tissue factor, they found the blood was hyper-susceptible to clotting. Then they added to the blood an agent designed to neutralize the tissue factor and ran it through the chamber again. "The clot didn't take place," Dr. Fuster says.

The results point to one of many targets that research into inflammation is identifying for potential treatment to avoid heart attacks. They also underscore a daunting challenge: Any new drugs will have to attack the harmful effects of inflammation while preserving its important benefits.

All of this offers a provocative hypothesis for how 70% of heart attacks happen. But what about the other 30%?

In the past two years, Dr. Fuster's group has devoted some of their attention to this problem, and they are investigating whether inflammation is at work here as well.

Scientists know that the high velocity of blood squeezing through narrowed arteries can strip away the artery's lining, leaving nothing but hard tissue. For a clot to form there, Dr. Fuster reasoned, the problem has to be in the blood itself, not the vessel wall.

In 1997, he heard a report from Renu Virmani of the Armed Forces Institute of Pathology in Washington, who had found that most victims of fatal heart attacks not involving a ruptured plaque either were smokers or had high cholesterol. Dr. Fuster decided to check whether cholesterol or smoke in the bloodstream could prompt clotting. His team ran blood from patients with high cholesterol through the Badimon chamber. "It began to clot in 10 seconds," Dr. Fuster says.

Dr. Fuster thinks some interaction between certain cells that are present in inflammation and the blood from these patients switches on a clotting mechanism. As the blood moving through the artery hits the section narrowed by a mature and stable plaque, it backs up and a clot forms, causing the heart attack.

Interestingly, he and his colleagues found, when blood from the same patients was tested again after they had taken statin drugs, very little clotting occurred.

The problem for both doctors and patients is that all of this action takes place beginning years before symptoms appear. "The Holy Grail of this field is to prevent the first heart attack from occurring at all," says Harvard's Dr. Ridker. He and his colleagues set out to use the inflammation research to find new indicators that might widen the net for patients at risk.

The problem for both doctors and patients is that a lot of this action takes place beginning years before symptoms appear. "The Holy Grail of this field is to prevent the first heart attack from occurring," says Harvard's Dr. Ridker. He and his colleagues set out to use the inflammation research to find new indicators that might widen the net for patients at risk.

A way to answer this question resided in a basement underneath a Thai restaurant on Boston's Commonwealth Avenue. There, stored in 60 stainless-steel cylinders at 170 degrees below zero Fahrenheit, were blood samples taken in the early 1980s from more than 22,000 doctors. This "Physicians' Health Study" had already produced a landmark finding: that a low daily dose of aspirin greatly reduced one's risk of a heart attack.

Now, the preserved blood samples enabled Dr. Ridker and his colleagues to travel back in medical time. They checked samples from 543 doctors who they knew eventually had heart attacks or strokes, to see what their levels of C-reactive protein had been about eight years earlier. Another 543 were picked as controls.

Using a test much more sensitive than those currently on the market, they found that men whose levels had been in the highest 25% when the study began were nearly three times as likely to have a heart attack as those who had the lowest levels. Moreover, those with high levels who also were taking aspirin -- which happens to be an anti-inflammatory drug -- benefited more from this aspirin than did men whose blood showed less sign of inflammation.

That raised new questions: Can C-reactive protein be lowered with treatment, and would lowering it mean that inflammation and heart-attack risk had also been lowered?

Once again Dr. Ridker looked to frozen samples, this time from a study Bristol-Myers Squibb did to find out whether its statin drug, Pravachol, reduced heart attacks and heart-related deaths (it did). Dr. Ridker found that C-reactive protein declined 38% over five years in people given Pravachol. And those who started with the highest levels of the protein showed the biggest reduction in heart attack risk.

This effect was independent of any changes in cholesterol, suggesting that statins have an anti-inflammatory effect that is protective, over and above their role in lowering cholesterol.

Dr. Ridker says his work suggests that by combining a sensitive test for C-reactive protein with standard cholesterol screening, "you could do a very good job predicting over the next 10 years who is going to have a stroke or heart attack." Maybe, he adds, "there is a rationale for much more aggressive primary prevention based on evidence of inflammation."

There are doubters. Thomas Kottke of the Mayo Clinic warns against thinking that just because certain patients have nice low levels of C-reactive protein, they are less vulnerable to high cholesterol, smoking, lack of exercise and a poor diet. "Those behaviors are associated with death -- I don't care what their C-reactive protein is," Dr. Kottke says.

Nonetheless, Merck & Co., which sells two statin drugs, is so intrigued that it has put an expert on inflammation in charge of its quest to find the next big heart drug. And Bristol-Myers, in seeking ways to broaden use of its own statin drug, is looking at arterial inflammation and at C-reactive protein as a sign of it.

Many heart patients at the Cleveland Clinic are tested for the protein now. "Once we started looking for it, we couldn't get over how frequent it was," says Eric Topol, chairman of cardiology. "We have all these patients with angiograms that look benign and cholesterols that are normal. But they have high inflammation."

Dr. Topol is trying to persuade the makers of the hot new class of arthritis drugs called COX-2 inhibitors to test them in heart patients. The drugs -- Celebrex from Monsanto Co.'s Searle unit, and Vioxx from Merck -- are anti-inflammatory drugs that behave somewhat like aspirin but in a more targeted way. Officials at Searle and Merck are interested but say that not enough is known yet to warrant a trial.

Many other questions about inflammation need answers as well, and finding them is likely to be a dominant theme of heart research for years to come. The case for inflammation is "not fully proven," Dr. Topol says. "But there's nothing more promising and exciting as the next frontier in cardiology than this."

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