January 17, 2011

Imaging Dangerous Plaque
By Beth W. Orenstein
For The Record
Vol. 23 No. 1 P. 24

Screening mammography followed by biopsy when indicated has helped reduce breast cancer deaths, especially in women over the age of 50. The reason is that early detection when cancer is small and contained leads to more effective treatment.

James E. Muller, MD, envisions his new technology helping reduce the number of heart attack deaths in a similar way. Muller is CEO and founder of InfraReDx Inc, maker of the coronary imaging system LipiScan, which can be used to identify and characterize lipid core plaques. Evidence is mounting that lipid core plaques are the most likely to rupture and cause a heart attack.

According to the American Heart Association, more than 1.25 million people experience heart attacks annually in the United States. More than one third die as a result, accounting for about one of every six deaths.

Muller wonders what would happen if older adults or people with a family history of heart disease would be screened using a noninvasive technique such as CT. “If you found partially blocked arteries on the CT, you could follow up with a LipiScan and determine whether they were the potentially dangerous lipid core plaques and then design appropriate interventions,” he explains.

The CT would be like screening mammography, he says, and the LipiScan would be analogous to a biopsy. In this way, he says, doctors may be able to reduce heart attack deaths much like they have deaths due to breast cancer. “I think the potential to build such a strategy is beginning to emerge,” Muller says.

Vulnerable Plaque
A professor of medicine at Harvard Medical School for more than 25 years, Muller has conducted research into the causes of sudden heart attacks in the hopes of finding a way to prevent them. In 1989, he introduced the idea of vulnerable plaque, or plaque that is most likely to rupture and cause a thrombosis.

Muller and his colleagues found that vulnerable plaques are generally rich in cholesterol, hence they have lipid cores. “Some plaques are collagen rich, and some plaques are lipid rich,” he explains. “The lipid core plaques are suspected to be vulnerable plaques.”

If a patient dies suddenly from a heart attack and an autopsy is performed, doctors are likely to find a clot and a lipid core plaque under the clot, Muller says. “In at least 65% of cases, that’s what happens. So there’s plenty of what I would call circumstantial and retrospective evidence that lipid core plaques are dangerous and are vulnerable plaque. Because they’re hard to measure in vivo, there is not a lot of prospective data,” he says. For example, an autopsy showed that well-known journalist and Meet the Press moderator Tim Russert had a hidden lipid core plaque that caused his fatal heart attack in 2008.

While the body of evidence is growing, lipid core plaques have not been proven to be the ones that can lead to sudden death. “I think it’s fair to say that lipid core plaques have been indicted but not yet convicted,” Muller says.

While an angiogram can detect blocked arteries, physicians are unable to distinguish lipid core plaques from collagen plaques while performing the procedure. Intravascular ultrasound (IVUS) allows physicians to look inside diseased arteries and can provide accurate information about lumen and vessel size as well as plaque area and volume.

“While IVUS is very good at detecting structure, it is not very good at detecting chemistry, with the exception of calcium,” Muller says. In the United States, IVUS is used in about 15% of cases where stents are needed to open blocked arteries that have been identified by angiograms. In other countries, such as Japan, IVUS is used in about 70% of cases.

Because not all plaques are vulnerable, Muller wanted to develop a device that would enable physicians to differentiate a collagen or a fibrous plaque from a lipid core plaque before a patient suffered a heart attack. That’s where LipiScan, the catheter imaging device that Muller helped design and build, comes into play. LipiScan received FDA approval in April 2008 and was launched commercially in January 2009. Since then, more than 700 catheters have been sold to 22 hospitals, according to Muller.

Near-Infrared Spectroscopy
LipiScan uses catheter-based near-infrared spectroscopy (NIRS) to assess the chemical makeup of the plaque found within artery walls during cardiac catheterization. Laser light from the catheter tip helps physicians determine how much fat and other substances are contained in a plaque. The device addresses many challenges of imaging a beating heart, including obtaining access to it via the optical fibers in the catheter, taking measurements through blood, and dealing with heart motion.

“The story of our small company,” Muller says, “is that over the past 12 years, we’ve overcome all of those obstacles. We now have made it possible for the physician to perform spectroscopic measurements of a beating heart of the patient through blood.”

Each year more than 2 million individuals worldwide undergo coronary stenting. While stenting procedures have steadily improved, approximately 30% of individuals experience a significant complication. But Muller did not create LipiScan to improve the safety of stenting. “We created it to find the plaque that causes heart attacks and kills people like Russert, who had passed a treadmill test months before his thrombosis,” Muller says.

But it turns out that the LipiScan device can improve the safety and efficacy of stenting procedures. The data show that about 20% of stenting patients experience issues within three years of undergoing the procedure, even if they’re prescribed a statin medication to reduce their cholesterol level. He says one half of the recurrence problem results from the stented site and one half results from an area that wasn’t treated initially.

“At the stented site, sometimes the trouble comes because the stent was put in or ends in a lipid core plaque. Physicians using our device can put in longer or shorter stents so that they don’t end in a lipid core plaque,” Muller says. “Our device enables them to judge the length of the artery to be stented.”

Sometimes the lipid core plaque is at the same spot as the narrowing detected on the catheterization and sometimes it’s not, Muller says. Generally, the lipid core plaque occupies about 4% of the length of the artery, or approximately 0.5 to 1 cm. LipiScan allows the physician to identify where the vulnerable plaque is and to stent the appropriate length of the vessel.

Future Possibilities
In about 10% of cases where patients undergo stenting, the plaque breaks off during the procedure as the physician blows up the balloon, travels through the arteries, and causes a heart attack. In most cases these heart attacks are small and harmless, but in rare cases they can be fatal. That’s why, Muller says, it is critical to know not only where the narrowing occurs but also what type of plaque is causing it. If the physician knows there is a high risk of plaque breaking off, he or she can alter the therapy. Muller notes that a study has been planned to examine using a downstream filter to catch debris and prevent a heart attack.

LipiScan could also help the interventionalist performing the stenting procedure to find additional lipid core plaques that should be treated. Likewise, Muller says, if further studies determine that lipid core plaques are responsible for heart attacks, physicians may be able to treat collagen or fibrous plaques differently. “At the moment,” Muller says, “the indications for placing or not placing a stent have nothing to do with lipid core plaques. … Plaques are stented when they limit the flow of blood through the heart. There is, however, a subset of smaller plaques that are on the borderline. They’re called intermediate stenosis, and they may be causing blockages of 40% to 50%. Because they do not interfere with flow, those plaques are not stented. If it could be determined that lipid core plaques are a danger waiting to happen, they might be treated even if current criteria suggest their blockage is not risky. More studies are needed to see what happens to people with lipid core plaques without blockage.”

Performing a LipiScan adds about 10 to 15 minutes to the stenting procedure. Muller says LipiScan is partially covered by insurance, in that Medicare and insurance payments would include all the equipment used during a catheterization procedure, including the LipiScan device. “However, it’s not directly covered,” Muller says, “because there is no additional payment for our catheter. We are working with the insurance companies to cover this usage. Our argument is that finding lipid core plaques and making stenting safer and preventing heart attacks will save money in the long run. It’s better to prevent heart attacks where possible, as heart failure and arrhythmias are both very expensive to treat.” Each LipiScan catheter costs approximately $2,400.

James A. Goldstein, MD, FACC, director of cardiology education and research at William Beaumont Hospital in Royal Oak, Mich., believes the era of stenting only where significant narrowings are found on angiograms may experience a paradigm shift in the future. “All that accomplishes,” he says, “is treating the obvious.” Once Goldstein’s patients have undergone stenting, many tell him their chest pain resolves. However, they all want to know, “Am I going to have another heart attack?”

“Therein lies the problem,” Goldstein says. “Treating only what is angiographically obvious misses other non–flow-limiting lesions that may be vulnerable and potentially lead to acute coronary syndrome or sudden death.”

CT Screening?
Goldstein agrees it’s necessary to find vulnerable plaques before they become unstable and cause catastrophic heart attacks. He was the lead author of a study published in the March 25, 2008, issue of the American College of Cardiology’s JACC: Cardiovascular Imaging that shows especially dangerous blockages could be found using CT angiography (CTA). In the study, 49 people came to the hospital with acute chest pain but without an obvious heart attack. They underwent CT scans that documented unstable plaques with a characteristic appearance that identified them as being dangerous. The findings were subsequently confirmed in all cases by invasive heart catheterization.
CTA could be used for initial screening, and IVUS and LipiScan could take the procedure even further, helping the interventionalist determine which narrowings must be stented, Goldstein says.

“Right now it looks like bulky, cholesterol-filled, thin-capped plaques are most vulnerable. The data isn’t in yet, but there is reason to believe that ultimately it will be shown that we can identify and treat those plaques likely to rupture, thereby preventing heart attacks. The way we’re doing it right now must be improved,” he says.

InfraReDx plans to integrate LipiScan and IVUS capabilities so that both the chemical composition and the structure of coronary plaques can be characterized simultaneously, facilitating coronary care decisions.

Brij Maini, MD, FACC, chair of the Structural Heart Program and cochair of cardiovascular research at PinnacleHealth system in Harrisburg, Pa., has been using LipiScan since the device received FDA approval in 2008. It adds time to the catheterization procedure, but “when the new catheters have the IVUS and LipiScan in one pullback, it becomes a very promising technique so that you’re saving a lot of time,” he says.

However, Maini says, “You have to consider how many modalities you’re going to use on a patient that require a lot of contrast and a lot of radiation. That’s something you want to take into consideration.”

To some extent, CT scans can find lipid core plaques, Muller says. “It’s not as accurate a detector inside the artery, but it could be adequate for screening,” notes Muller, adding that he’s disappointed equipment manufacturers don’t seem interested in studying the use of CTA as a screening measure for vulnerable plaque. “I’m not sure why that is,” he says. “I guess it could be that CT is used for so many other purposes that this only gets a small amount of attention.”

But Muller hopes that within a few years, people will look to imaging techniques to help prevent heart attacks just as they rely on screening tests that can detect cancer in its early, most treatable stages. He believes prevention is the best way to keep healthcare costs from spiraling out of control. Imagine, Muller says, what it would mean if researchers found a better way to detect heart attacks waiting to happen.

“LipiScan will have to prove its role in preventing second heart attacks before it’s used as a primary tool,” he says, “but that day may not be that far off.”

— Beth W. Orenstein is a freelance writer based in Northampton, Pa.