Clogged arteries start early in males -- Vulnerable Plaque

Cardiac Imaging

Future of CVI: It’s all about plaque
Identification of vulnerable lesions, not ‘rusty pipes,’ could become cornerstone of preventive cardiology

By Catherine Carrington

Sidebars:
Noninvasive angio: Will CT rout MR?
PET goes subcellular
Future may include CV interventions

Think of a pump fed by a network of pipes so rusty and corroded that only a trickle of fluid finds its way through the constricted core, until finally the pump seizes up and stops working. That’s how scientists once viewed the cardiovascular system and its most extreme example of deferred maintenance, the heart attack.

Today, we know the picture is far more complex. Most heart attacks aren’t caused by a slow, occlusive build-up of atherosclerotic “rust,” but rather by the sudden rupture of weakened plaque silently festering with inflammation [Fig. 1]. What’s more alarming, rupture-prone plaque seldom narrows the coronary “pipes” much or interferes with blood flow, and that makes it undetectable by conventional diagnostic methods.

“The microanatomic characteristics of plaque composition may be more important than the severity of the stenosis in the angiogram,” said Dr. Pedro Moreno, who directs the catheterization laboratory at the Veterans Affairs Medical Center in Lexington, KY. “Unfortunately, regular angiography is not able to detect this lesion.”

That realization is changing the face of cardiovascular imaging. Characterizing plaque has become the relentless focus of nearly every form of cardiovascular imaging. It is fueling research not only in MR, CT, ultrasound, and nuclear medicine, but also in novel invasive approaches that exploit the potential of light, heat, and chemistry to distinguish stable, calcified plaque from soft, vulnerable lesions that are filled with fat and inflammatory cells and encased by only a thin, fibrous cap.

Noninvasive methods of plaque characterization are especially appealing, and MR brings certain advantages to the task. Its spatial resolution, though not as impressive as that of its invasive competitors, lets it image plaques smaller than 1 mm.

[Karl Note:  Note that the thickness of the cell membrane is about 10 nm, nanometers.  In comparison, the plaque being "found" here is 1 mm in size.  One mm is 1/1000th of a meter.  One nm is 1/1,000,000,000 of a meter.  Obviously this method of measuring is NOT going to "SEE" something as small as the membrane of a cell!  So, while this whole article can be completely valid and useful, and whereas the detection of so-called "vulnerable plaque" is useful, there is no reason within this why all of this "plaque" could not be WITHIN cells, rather than OUTSIDE cells.

Even though the plaque is INSIDE cells, those CELLS could rupture and that would be what is talked about here.  Dr. Garry F. Gordon is very familiar with this process and suggests that this "rupture" is, basically, an inflammation of these cells and could easily be handled by using oral chelation and a special anti-inflammatory, called "FYI" or "For Your Inflammation."  FYI is available from Vibrant Life -- click here.]

It can create both two- and three-dimensional images. And it is also capable of quickly assessing atherosclerosis throughout the body, a key strength in gauging the risk not only of heart attack but also of stroke, which can result from plaque rupture in the carotid arteries and aorta.

“It’s very important to have an imaging modality that can assess this disease in a systemic fashion,” said Zahi Fayad, Ph.D., who directs cardiovascular imaging physics and research at Mount Sinai Medical Center in New York City.

MR differentiates components in the plaque through natural tissue contrast arising from differences in chemical composition. Each of the four main components of plaque—calcium, lipid, the fibrous cap, and thrombus—scripts a different signature on the MR sequences used to image it. From this information, it may be possible to predict which plaques are stable and which are vulnerable to rupture.

[Karl Note:  Again, this careful description of FOUR different types of material leaves out, obviously, the membrane of the cell -- leaving, again, open the probability that all of these materials are INSIDE cells, rather than OUTSIDE.]

Calcium, for example, has very little water and few protons, so it looks hypointense on T1-weighted imaging and very hypointense on both proton-density and T2-weighted imaging. A plaque’s threatening lipid core, by comparison, appears very hyperintense on T1-weighted imaging, hyperintense on proton-density imaging, and very hypointense on T2-weighted imaging. The fibrous cap looks isointense or hyperintense with all three imaging sequences, while the appearance of thrombus is variable.

Though MR leads noninvasive plaque evaluation, CT can add important details to the picture, and preliminary research suggests it may, in the future, offer information on plaque composition as well.

When information from MR and CT is pieced together, it will offer valuable insight into vessel wall pathology, experts predict.

[Karl Note:  The author, here, refers to "vessel wall pathology," which is a valid term, but the tests being described DO NOT detect the vessel walls themselves, but see only the materials that would be INSIDE those vessels.  The word "vessel" often refers to the entire artery, rather than just one cell, but even with this definition, the "pathology" of the "vessel" can be nothing more than the pathology of individual cells -- for it is the cells that make up the artery.  The artery does not have an existence separate from the individual cells.]

“I believe that we will have noninvasive techniques mastered in the next three to five years,” said Dr. Tom Brady, who directs the cardiac imaging program at Massachusetts General Hospital in Boston. “When people go into the cath lab in 2007 or even earlier, they will have not just the ‘lumenogram’ provided by conventional angiography, but a map of wall thickness, plaque volume, lipid volume, and calcium volume displayed for the cardiologist.”

The View From Within

Despite the advantages of noninvasive imaging, the most accurate way to characterize plaque so far appears to be up close and personal. MR researchers know this and are working on invasive and interventional MR technologies. Fayad and his colleagues, as well as researchers at Johns Hopkins Hospital in Baltimore, are testing the potential of high-resolution intravascular MR coils mounted inside of catheter guidewires, for example.

Invasive MR faces competition from a number of novel invasive techniques that are vying to establish their scientific validity.

“Our information regarding the atherosclerotic plaque largely comes from cross sections obtained at autopsy,” said Dr. E. Murat Tuzcu, who directs the intravascular ultrasound laboratory at the Cleveland Clinic. “All of us are trying to get a glimpse of the action when the patient is living and awake. Down the line, I think we will rely less on taking care of patients after a catastrophe than on trying to prevent it.”

[Karl Note:  When an autopsy is done, and a "piece" of an artery is removed for examination, there is a cross section that might be the size of a wooden pencil.  Within that cross section you would find the "plaque."  Again, this "plaque" can be either WITHIN or OUTSIDE the individual cells, and the only difference between these two locations would be the wall of the cell -- a wall that is about 1/100th the size of a human hair and is too small to be seen with visible light.  Again, it seems very possible that this "cross section" can accurately measure the large items, like the calcium, etc., but could never ever see the membrane walls.  So, there is nothing here which precludes the possibility that plaque is INSIDE cells, not outside, and therefore the origin of this plaque would likely be very different from what scientists have been claiming for years!]

Of the invasive approaches, intravascular ultrasound (IVUS) has the longest track record and is often cited as the imaging gold standard for plaque identification, offering tomographic images that visualize many of the characteristics defined by pathologists at autopsy.

[Karl Note:  The reference here to "gold standard" seems to relate to the measurement of plaque during an autopsy -- that measurement, as shown in my comments above, is very unlikely to detect cell membranes -- so one can assume that none of the other measuring techniques will be able to see cell walls either!]

With IVUS, plaque is characterized according to the degree of echogenicity in comparison with normal adventitia. Soft, lipid-filled plaque is less echogenic, and calcified plaque demonstrates a bright echo and acoustic shadow. But Tuzcu cautioned that ultrasound is limited in the details provided.

“Ultrasound gray-scale pictures do not always represent faithfully the histologic changes,” he said. “On the other hand, intravascular ultrasound is very accurate in determining the location of plaque and whether it is eccentric or concentric.”

One of the most promising new technologies is optical coherence tomography (OCT). This is akin to IVUS but measures back-reflected infrared light rather than sound. It is a high-speed technology whose simple fiber optics are incorporated into existing arterial catheters. Its key advantage over IVUS and many other techniques is an extremely high resolution, 4 to 20 mm.

[Karl Note:  Again compare the "small" size of what the IVUS can detect (4 mm) to the very tiny size of a cell wall (10 nm)!]

“That’s up to 25 times higher than anything in clinical medicine,” said Dr. Mark Brezinski, a researcher at Brigham and Women’s Hospital in Boston.

This means that while IVUS may detect plaque, OCT can visualize its makeup in detail, including the layers of intima the plaque has invaded and the thickness of its fibrous cap—a key in assessing the risk of rupture [Fig. 2]. A fibrous cap that is less than 65 mm thick is considered to be at high risk for rupture, according to pathologist Renu Virmani of the Armed Forces Institute of Pathology in Washington, DC.

Human trials of OCT are expected to begin in late summer, said David Kolstad, marketing vice president of LightLab Imaging, a company founded by Brezinski and others to commercialize OCT technology.

A Biopsy With Light

At the University of Kentucky, researchers are testing the potential of near-infrared (NIR) spectroscopy to go beyond creating an image of plaque and, instead, provide information on its chemical and molecular structure.

When plaque is illuminated by halogen or laser light from a fiber-optic probe tuned to the NIR wavelength, some of the light is absorbed by the plaque, but most is scattered back. Once captured by a receptor, scattered photonic energy is dissected into different wavelengths.

“We have these absorbent peaks that usually are produced by combinations of fundamental bonds, like carbon-hydrogen, carbon-carbon, and carbon-oxygen. These bonds actually stretch with light and induce these peaks,” said Moreno, an assistant professor at the University of Kentucky, where the research is being conducted.

The technique has demonstrated high sensitivity and specificity for identifying vulnerable plaque in laboratory and animal studies. Moreno expects to begin human studies by the end of this year. Down the road, researchers are planning to conduct a 1000-patient trial to gauge how successful NIR spectroscopy is in predicting clinical outcomes, not just in patients at risk for plaque rupture but also for a related condition known as plaque erosion.

Erosion is a thrombotic process in which the plaque appears more stable than it really is. The plaque is not filled with lipid and the fibrous cap remains intact. The endothelium is worn away, however, exposing the intima to blood. Erosion is believed to account for 40% to 50% of plaque thrombosis, particularly in young women and smokers.

“We will follow those patients that we thought had stable plaques,” Moreno said. “Some of these patients will evolve with an acute syndrome, and the NIR signal could be analyzed retrospectively to finally detect a plaque that is not only vulnerable for disruption but also vulnerable for erosion and thrombosis.”

Inflammation plays a key role in the destabilization of plaque. The coronary arteries don’t have pain fibers, and both swelling and redness can have many other causes, according to Dr. S. Ward Casscells III, cardiology chief at the University of Texas Health Science Center in Houston.

“Fortunately, heat remains a valid sign of inflammation in the coronaries—and the heat is more than anyone might have predicted,” Casscells said.

Casscells and his colleagues have analyzed arterial specimens immediately after surgical removal and noted temperature increases in the plaque of up to 2ºC. Heat variation in plaque is correlated most closely with the number and activity of inflammatory cells and the thinness of the fibrous cap. A thick cap acts as an insulator, but a thin cap places inflammatory cells close to the lumen.

To measure the heat generated by inflamed plaque, Dr. Morteza Naghavi, Casscell’s colleague at UT, has led the development of an intravascular thermography catheter equipped with infrared fibers [Fig. 3]. Researchers in Greece have developed a similar device and have demonstrated striking differences in the temperature of plaque between patients with stable angina and those with unstable angina or myocardial infarction.

In the future, such catheters may also be used to treat thrombosis-prone lesions—ironically, by heating them even more.

“If you raise the temperature a little bit higher to 41° or 42°C (106° to 108°F), you see that the inflammatory cells, the macrophages, preferentially undergo apoptosis,” Casscells said. “Presumably this is a good thing, since these are the cells that eat through the cap and cause the thrombosis.”