Is This Artery About To Blow? The biggest heart-attack villain is a kind of plaque you've never heard of. The race to find it is on.
By Timothy Gower

(FORTUNE Magazine) – One night in the spring of 1993, University of Texas cardiologist Ward Casscells stayed up late, lighting matches and burning the skin on his inner left arm. Earlier that evening he'd been tending his 2-year-old son, Max, who had an ear infection. Using a special infrared thermometer, Casscells had discovered that the boy's inflamed ear was one degree hotter than the healthy one. He started to wonder: Could a thermometer also detect inflammation in the arteries--which some of his more daring colleagues were starting to say was the true cause of heart attacks?

To test his theory, the widely respected scientist began playing with fire. Using the same thermometer, he learned that it was possible to tell his burns from uninjured flesh simply by taking their temperature. By dawn he was convinced that finding hot spots in the cardiovascular system just might help prevent the leading cause of death in the Western world. "It was a great day in my life, that's for sure," says Casscells, sitting in his Houston office nine years later and rolling up a pinstriped sleeve to reveal a cluster of souvenir scars.

Crazy? That's what the medical establishment used to think of Casscells and maverick scientists like him. But these scientists have rewritten textbooks by debunking one of the most deeply ingrained ideas in medicine: that heart attacks--which strike one million Americans every year and kill half of them--are caused by clogged pipes. Eat too much junk food, doctors long believed, and eventually the arteries become filled with cholesterol and other gunk. Over time, these masses (known as plaques) become so large that they cut off blood flow to the heart. Starved of oxygen- and nutrient-rich blood, the heart muscle begins to die. If you don't make it to the ER in time, so do you.

Scientists now know that most heart attacks don't happen that way. Clogged arteries do cause chest pain and other unpleasant symptoms, but they are responsible for no more than 15% of heart attacks. Instead, the far deadlier culprits lie embedded in the walls of the pipes themselves: deposits of a certain kind of plaque that don't cause symptoms--since they don't dam up blood flow--but that can become inflamed, swell, and rupture without warning. These ruptures lead to blood clots. Some dissipate quickly, but others may block blood flow to the heart, causing an attack. Plaque can erupt from the walls of neck arteries too, causing strokes, the third leading killer in this country. Because of the volatile nature of these deadly lesions, some scientists have christened them "vulnerable plaques."

Why don't doctors simply hunt down and destroy these vascular villains? Here's the scary part: Right now, standard imaging equipment and screening tests used to detect signs of cardiovascular problems simply aren't sophisticated enough to locate them. So makers of medical devices are racing to develop and bring to market tools that can find--and fight--vulnerable plaque. Much of the cutting-edge research is happening at startups, such as Volcano Therapeutics, a Laguna Hills, Calif., company created by Casscells and others. Volcano is building tiny heat-seeking sensors that can be guided into the arteries with a catheter. Medical-imaging giants are on the plaque attack too. GE Medical Systems, Siemens Medical Solutions, and Philips Medical Systems, for instance, are scrambling to upgrade their magnetic resonance imaging (MRI) and computed tomography (CT) technology, either in-house or through partnerships with researchers at leading medical centers, to detect vulnerable plaques before they kill. The rewards could be huge; some industry insiders say the market for finding and treating vulnerable plaque could reach $10 billion by the end of the decade.

Lest you think that bacon and bearnaise sauce are now off the hook, be warned that a lousy diet can help form vulnerable plaque. The process goes like this: As cholesterol courses through the blood, it can lodge within artery walls. A cap of fibers forms over these fatty pools, protecting them from exposure to the blood. Trouble starts when the immune system launches an assault on the embedded cholesterol--the phenomenon known as inflammation--sending voracious defender cells called macrophages to devour the cholesterol. As the inflammatory cells burrow through the protective cap, it can weaken and rupture, triggering those dreaded clots.

Unfortunately, when it comes to vulnerable plaque, your doctor's diagnostic arsenal is mighty weak. Angiography, the current gold standard for diagnosing cardiovascular problems, shows where blood vessels have narrowed but cannot peer inside the walls of the arteries where vulnerable plaque dwells. Neither can currently fashionable electron-beam CT scans. And blood tests for cholesterol, while still essential, allow a lot of people at risk to slip through the cracks; half of all heart attack victims have normal cholesterol readings.

Here's another test you may want to take: one that measures your blood level of C-reactive protein (CRP), a substance produced wherever there is inflammation. Studies show that people with normal cholesterol, but high CRP, have an increased risk of heart attack. Three years ago, Dade Behring, a medical-product maker in Deerfield, Ill., introduced a simple $50 blood test for CRP; the company sold $20 million worth of the tests last year. Two other manufacturers, Diagnostic Products Corp. and Beckman, make similar tests. When more comprehensive studies are completed in five years or so, CRP testing could become as ubiquitous as cholesterol testing, for which private insurers pay out more than $700 million per year, according to Medstat in Ann Arbor, Mich. Peter Libby, chief of cardiovascular medicine at Boston's Brigham and Women's Hospital, says that CRP testing may someday help "pick out the 'walking well' who might respond to drug therapy."

But some cardiologists say it's not enough to know simply that your arteries are inflamed; you must find the exact spots where vulnerable plaque lurks if you want to treat it effectively. A wave of diagnostic tools will soon hit the U.S. market to enable doctors to do just that. During the next year, four privately held startups in the U.S. and another in Europe plan to introduce high-tech plaque-detecting devices built for use with slender, hollow tubes known as catheters. Cardiologists already employ catheters to perform common procedures such as angiograms and balloon angioplasty (in which a tiny balloon is snaked into an artery--typically starting from the femoral artery, next to the groin--and inflated to open a blocked vessel).

Since two million to three million such procedures are performed around the world each year, these young companies hope to convince cardiologists that scanning for vulnerable plaque in patients who are undergoing cardiac catheterization anyway could prevent thousands of heart attacks. Single-use, disposable catheters are expected to sell for $500 to $1,000 each. According to Kenneth McDonnell, vice president of business development for InfraReDx, a catheter developer in Cambridge, Mass., worldwide sales of plaque-seeking catheters could reach $1 billion a year by the end of the decade. His company aims for $200 million in revenues by 2007.

Competing catheters work slightly differently. InfraReDx, founded by James Muller of Massachusetts General Hospital, the cardiologist who coined the term "vulnerable plaque," makes catheters that use lasers to create a kind of topographical map of fatty deposits in arterial walls. Catheters from LightLab, a 13-person Westford, Mass., firm established in part with seed money from optical manufacturers Pentax Corp. and Germany's Carl Zeiss, create cross-section images by firing light in all directions inside the artery, then recording how much is absorbed and reflected by surrounding tissue.

Instead of capturing images, the catheter from Casscells' company, Volcano Therapeutics--whose investors include Johnson & Johnson and Medtronics and which forecasts revenues of $250 million by 2006--detects heat. Studies have confirmed Casscells' hunch that vulnerable plaque is slightly warmer than healthy artery tissue. Thermocore in Belgium is developing heat-sensing technology too. Imetrx in Silicon Valley is working on an alternate way to detect hot blood vessels--"bio-profiling," or using a probe at the catheter's tip to find the chemical receptors in an artery to which inflammatory molecules attach themselves.

Some doctors, however, say that catheters will never offer a practical way to find vulnerable plaque in people who have no symptoms of cardiovascular trouble. "You're not going to volunteer to shave your groin and have someone stick a needle into an artery and rummage around in your heart for nothing," points out cardiologist Libby. There are noninvasive ways to look inside the blood vessels, but CT and MRI machines don't have a proven track record of detecting vulnerable plaque in the tiny coronary arteries.

So Valentin Fuster, director of the Cardiovascular Institute at Mount Sinai School of Medicine in New York City, hired engineer Zahi Fayad away from the University of Pennsylvania to make MRI more plaque-sensitive. Fayad's team of ten engineers and technicians has been working with Siemens--which manufactures the MRI machines Mount Sinai uses--to rewrite software and tweak hardware to produce sharper images. Fayad also developed a technique known as "black blood" imaging that overcomes a problem with standard MRI technology, which shows both blood and vessel walls as white. Fayad's innovation allows him to see where the vessel wall has thickened--a marker for vulnerable plaque. Mount Sinai's cool new tool is still considered experimental; it could be a few years before your doctor has access to similar technology.

Other researchers are working to adapt MRI machines to spot dangerous plaques, but it will be at least three to five years before any of these innovations are available, either. At Houston's Center for Vulnerable Plaque Research, part of the Texas Heart Institute, cardiologist Morteza Naghavi is studying iron-containing nano-particles that, when injected into a patient, "tag" areas of inflammation. Likewise, Philips Medical Systems is collaborating with scientists at Washington University in St. Louis to develop injected particles that cause fibrin, a protein produced during blood clotting, to light up on an MRI. And GE Medical Systems distributes a product developed by Surgi-Vision, a Gaithersburg, Md., company--a tiny, antenna-like wire that's threaded into a blood vessel and enhances the ability of MRIs to diagnose certain circulatory diseases; it also shows promise as a plaque hunter.

When cardiologists talk about the race to detect vulnerable plaque, they always come back to the same question: How do we treat it once we find it? The answer may turn out to be right under their noses, says InfraReDx's James Muller, who also oversees one of the world's largest vulnerable-plaque research programs at a consortium of Boston-area hospitals and labs called the Center for Innovative Minimally Invasive Therapy (CIMIT). If doctors could identify patients with vulnerable plaque today, Muller says, they could treat the disease with two current cardiovascular superstar therapies, either alone or in tandem: stents and statins.

To decide which to use, a doctor would first determine how vulnerable your plaque really is. If it has thin caps that appear ready to burst at any second, doctors could reinforce them with stents. These tiny wire-mesh tubes are designed mainly to prop open narrowed arteries, but cardiologists in Europe are already using stents to prevent plaques from rupturing. (A patient with lots of stents is said to have a "full metal jacket.") Some cardiologists are leery of stents because of their high failure rate; they allow arteries to reclog in 30% to 50% of patients. But Johnson & Johnson, Medtronics, and Indianapolis medical-equipment maker Guidant will begin selling drug-coated stents in the U.S. by next year (potentially doubling the market for the devices, to $5 billion in annual sales). Early reports suggest that medicated stents will have a much lower failure rate.

On the other hand, if you have vulnerable plaque with thick caps--meaning they are probably not ready to burst--your doctor might treat it with statin drugs, which take about six months to become effective. These wildly popular pharmaceuticals, such as Pfizer's Lipitor, Merck's Zocor, and Bristol-Myers Squibb's Pravachol, which rack up nearly $12 billion in annual sales, appear to provide a double whammy. Not only do they suck cholesterol out of plaques, but they may also relieve inflammation, which would help explain their impressive ability to prevent heart attacks.

Since taking statins probably won't hurt (side effects, including liver and muscle damage, are rare) and might very well help, should those of us worried that we might have undiagnosed vulnerable plaque start popping the pills now? Well, few doctors will put you on statins if you don't have high cholesterol, since no studies yet exist to prove their effectiveness in people with normal cholesterol readings. But several noted cardiologists have publicly acknowledged that they take statins--even though their cholesterol is fine--just in case. Peter Libby himself half-jokingly asks, "What do we do? Put statins in the drinking water?"

Down the road, vulnerable plaques may also be eliminated by catheters. Volcano is testing a device on animals that delivers heat to vulnerable plaques, based on Casscells' theory that warming the lesions could have the paradoxical effect of shutting down inflammation. And if heat works, why not light? Pharmacyclics, a public company in Sunnyvale, Calif., is developing a combination drug-and-catheter system that would knock out vulnerable plaques with a one-two punch. A patient would first take a drug called Antrin, which is absorbed by inflammatory cells that invade vulnerable plaques. Next, a physician would illuminate the inside of the arteries by inserting a laser-tipped catheter. The light activates Antrin, which causes the inflammatory cells to literally commit suicide before they do real harm. CEO Richard Miller foresees a multibillion-dollar market for Pharmacyclics' plaque therapy, but it won't be available for at least five years.

By that time, the diagnosis, treatment, and prevention of heart disease will have changed dramatically, experts say. Assuming privacy issues can be worked out, genetic testing will help identify patients whose DNA increases their odds for suffering the Big One. (The University of Texas Medical Center has already begun collecting genetic samples from patients in order to build a DNA profile of potential heart-attack victims.) Scientists like Naghavi see endless possibilities for preventing heart attacks. "We're 100% sure we can develop a vaccine against heart attacks," he says, perhaps by developing a drug that teaches the body to reduce production of molecules that cause blood clots. Naghavi also wants to develop a kind of dialysis that would sift out deadly sludge before it collects in artery walls. Within a few years, he believes, consumers will be able to walk into any drugstore and buy an inexpensive at-home test that analyzes up to 50 risk factors for cardiovascular disease with just a pinprick of blood. "These are not Star Trek projects," he insists.

For now, however, here's your best advice: At your next checkup, ask your doctor about a CRP test. It's worth talking about statins too. In the meantime, exercise, don't smoke, and really, really try to like tofu.