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An Interview with Szilard Voros, MD

As coronary imaging turns to intravascular technologies -- views from inside the arteries themselves -- new fields of research and clinical study have opened. One of these new technologies is Virtual Histology IVUS and Angioplasty.Org recently sat down with one of the leading researchers in VH IVUS, Dr. Szilard Voros.

Dr. Voros is the medical director for Cardiovascular Magnetic Resonance (CMR) and Computed Tomography (CCT) at the Fuqua Heart Center of Atlanta at Piedmont Hospital, dedicated to providing world-class non-invasive imaging of the heart and blood vessels. Dr. Voros utilizes the latest technology to detect cardiovascular disease and collect life-saving information available in the past only through invasive procedures, such as cardiac catheterization and invasive coronary artery angiography.

With years of experience in these new and exciting fields, Dr. Voros has published extensively in clinical as well as investigational aspects of CMR and CCT. He is a founding member of the Society for Cardiovascular Computed Tomography (SCCT) and is a member of the Society for Cardiovascular Magnetic Resonance (SCMR). Dr. Voros has published extensively in the field of advanced cardiovascular imaging and regularly lectures at national and international meetings.


An Interview with Szilard Voros, MD
Szilard Voros, MD
Fuqua Heart Center at Piedmont
Hospital, Atlanta, Georgia

Q: Cardiologists certainly are familiar with intravascular ultrasound (IVUS) but what is Virtual Histology IVUS, or VH IVUS, and how does it work?
Dr. Voros: It's an ultrasound-based technique. Ultrasound is obviously used for a lot of different applications. But this just happens to be intravascular, so it's a small ultrasound probe that actually is placed on the tip of a catheter that can be then advanced into the arteries that feed the heart. Once the transducer is inside the artery, it functions just like any other ultrasound, except obviously since it's inside, it's taking pictures from the inside out as opposed to from the outside.

It's an ultrasound probe so it sends out ultrasound frequencies, sound waves, and then these sound waves are reflected back from different components of the vessel wall, which is what we're interested in looking at. When these sound waves bounce back, much like an echo as when we're screaming in the mountains, then we can detect these waveforms that are reflected back. And there are several features of the sound waves that come back that we can measure. For example, we can measure the amplitude and the frequency of these sound waves. Specifically using the amplitude is how we create the grey scale images in standard IVUS.

Now what VH does is look at a different layer of information in this reflected sound wave information that comes back. This so-called radio frequency backscatter information is then translated into a color scale with the idea behind it that different tissues have different characteristics as to how they reflect the sound waves back. So, as we unravel this radio frequency backscatter information, it gives us an idea of the composition of the different tissue types within the vessel wall. That's the general idea.

Q: Is there special equipment or hardware needed to produce VH IVUS, or is it mainly a software interpretation of the same data you’d get from a standard IVUS imaging catheter?
Dr. Voros: There are several vendors out there that make IVUS catheters. Essentially the way you interpret the information that comes back, some of that is hardware, but most of that is software interpretation. Specifically VH-IVUS is an algorithm only available from one of the vendors.

VH IVUS shows color-coded plaque composition:
red is necrotic core, dark green is fibrous, light
green is fibrofatty and white is calcified plaque.
The grey circle around these plaques is the
vessel wall. The black inner oval is the open
diameter of this blocked artery

Q: Four types of plaques are listed as to what VH IVUS can identify: dense calcium, fibrous, fibrofatty and necrotic. What are those and what are the clinical implications for the patient.
Dr. Voros: Actually those particular classifications are vendor-specific, however, those are general components of plaques that, if you look at a histological section of an atherosclerotic plaque, which we do all the time in our research efforts, we find the same components. Obviously the nomenclature is corresponding to that. In fact VH-IVUS was validated and the algorithms were developed on the basis of these histological sections.

Essentially the quick overview is that atherosclerotic plaques develop because of two primary processes: number one is what we call lipoprotein deposition in the plaque. It's just the cholesterol-rich particles that are deposited. That's the primary process. But this process also fuels the recruitment of inflammatory cells, so inflammation is the second component. These two processes go hand-in-hand for a while.

But then, as those processes progress, part of this plaque on the inside of the vessel wall starts to undergo what's call apoptosis or necrosis, meaning the cells start to die. So you have this necrotic core within the plaque. So that's essentially the area where there are no cells left -- only the cholesterol debris and the cholesterol crystals and a lot of the cell debris. As that process continues, the cap that separates the plaque from the blood pool gets thinner and thinner, so you can have micro-ruptures of that, you can have small areas of bleeding or hemorrhage into the plaque. Eventually, the healing of the small micro-hemorrhages and some other processes may result in calcification. So in general the way to think about this is that calcification is a later stage manifestation of atherosclerosis. A lot of people think of calcification as actually the healing process per se. So, what we know about are the non-calcified components, which are the necrotic core, the fibrous and the fibro-fatty tissue, those are the non-calcified areas. Typically they are associated with earlier stage atherosclerosis and in general more vulnerable plaques. Whereas calcification typically represents later stage disease and actually a healing process.     VH IVUS Image
Another VH IVUS image shows a vessel with
85% plaque burden -- the actual vessel, shown
by the grey oval is around 5mm, but the
opening, shown as the black inner oval, is
only 2.1mm. Virtual Histology reveals the
composition of the significant plaque, which
cannot be seen on a standard angiogram.

Q: There's a lot of controversy about what causes thrombus or clot to form in the coronary artery, resulting in an acute myocardial infarction (AMI) a.k.a. a heart attack. On an angiogram, you see a blockage. But recent discussions have been focused on this thin capped fibrous atheroma (TCFA) or so-called vulnerable plaque, which could rupture, spill lipids into the blood flow and quickly cause thrombus to start forming.
Dr. Voros: The way I look at that is there's this paradox: the current paradigm in cardiology, cardiovascular disease, is what I refer to as the hemodynamic paradigm. And what that paradigm says is that if you have an obstructive lesion greater than 70% diameter stenosis, then that leads to flow limitation. Therefore you have ischemia which causes you chest pain. If I relieve this obstruction by angioplasty, then this ischemia goes away, the perfusion is then normalized, so your chest pain goes away, and you live longer. This is the paradigm that framed our thinking in cardiology for 30 years which is the basis of angioplasty and bypass surgery.

The paradox is what we learned back in the 1980's from the thrombolytic literature; back in those days we did not do primary angioplasty, we did thrombolytics -- when we gave thrombolytics, the clots resolved. So when people looked at arteries that were closed at the time of the acute infarction, oftentimes the underlying culprit lesion, on which the thrombus formed and which occluded the artery, the underlying culprit lesion in the majority of cases was a less than 70% stenosis. In other words there was this paradox where we knew what to do with the obstructive plaques. However, up to 70% of these infarct-related lesions were actually non-hemodynamically significant.

So to that effect, we're conducting the ATLANTA study in my lab, which is focusing on non-obstructive plaques. We’re studying these non-obstructive plaques between 40-70% very carefully. We're characterizing these plaques in the CT labs, using CT coronary angiography. Then we take the patient to the cath lab. In the cath lab we measure the hemodynamic significance of the lesion by performing Fractional Flow Reserve (FFR) to truly understand the hemodynamic significance. Then we do IVUS and VH-IVUS to look at the composition of the plaque.

It's a longitudinal study so we're following people up and so we're trying to understand what is the significance of having, for example, VH TCFA or VH necrotic core and trying to understand what is the natural history of disease. From retrospective studies we know that when people compared so-called stable plaques vs. unstable plaques, meaning plaques that had events associated with them or not, when they retrospectively compared their baseline features, in general, lumen area, lumen diameter, percent diameter of stenosis, percent area of stenosis did not differ from unstable to more stable plaques. But things like positive remodeling, plaque burden, such as percent atheroma volume, were higher in the unstable plaques. Also from a VH composition perspective, these so-called unstable plaques had more TCFA and lipid-rich necrotic core, compared to the stable lesions.

Q: And the different between stable and unstable lesions can be visualized how?
Dr. Voros: These were retrospective studies, so researchers looked at patients who a year or two before had an IVUS and VH, and in the following one or two years they had an event related to a plaque or not. And then they went back retrospectively to look at the underlying features there. So it was clinical definition for stable vs. unstable plaques. Now these retrospective studies told us, okay if you look lesions that ended up causing an event, in general they were more positively remodeled, in general had more percent atheroma volume, in general had more necrotic core and in general had less calcium than lesions that did not cause events. The difficulty at this point is that we see a lot of those lesions that are positively remodeled, have a lot of PAV (percent atheroma volume), have a lot of necrotic core, and some of them do go on having events and some of them don't. So we still need to further refine some of these features to predict events.

Q: Where is the ATLANTA study at right now, and what does the acronym stand for?
Dr. Voros: We are in the second phase of the study. The first phase focused in patients with 40-70% lesions. The second phase is focusing on the high grade lesions over 70%. And the acronym stands for: Assessment of Tissue Characteristics, Lesion Morphology and Hemodynamics by Angiography with Fractional Flow Reserve, Intravascular Ultrasound and Virtual Histology and Non-Invasive Computed Tomography in Atherosclerotic Plaques.

Q: I see why this study needs an acronym. You’re using virtually every imaging technology that exists. A few years ago, Prof. Patrick W. Serruys of the Thoraxcentre in Rotterdam said, "Plaque imaging using VH IVUS will provide key information and may shift the paradigm of how we diagnose and manage patients with cardiovascular disease." How close are to Prof. Serruys’ prediction?
Dr. Voros: We're getting there. I think we're learning and, as with most everything, it's not as simple as we originally thought. But nevertheless, here's my underlying take on VH IVUS. There has been some discussion as to how accurate it is. When you actually look at VH IVUS and then you look at human tissue, how accurate is the algorithm in classifying parameters. In some of the original work it was pretty robust. There were sub-studies published recently that said maybe it's not so robust in characterizing tissue. From a clinical perspective it doesn’t really matter, as long as whatever you see does in fact predict clinical events. I think that we don’t have that answer today yet and I think we have to have the PROSPECT study completed before we can tell whether or not Patrick's statement is going to be a reality or not.

Q: Are you involved in the PROSPECT study?
Dr. Voros: We were part of the PROSPECT study site here at Piedmont. They also collect a subgroup of PROSPECT who had CT angiography as well as VH IVUS. Our ATLANTA study is sponsored by the same organization that funds PROSPECT, so there has been some discussion in potentially combining the data sets.

Q: Is VH IVUS still basically a research tool?
Dr. Voros: Yes. I think that's a fair statement. Of course, it is an FDA-approved product and I do know that some physicians make their treatment decisions based on their VH IUS, but honestly there has not been a single randomized prospective controlled strategy trial that looked at the outcomes from whether or not you made your decision based on VH IVUS or not.

Piedmont Hospital
Piedmont Hospital
Atlanta, GA

Q: Do you or the people in your department find VH IVUS useful for making clinical decisions?
Dr. Voros: We most certainly look at it. We most certainly take it as one piece of the puzzle. There are a lot of things we know about the patient: we know their clinical history, we know typically the myocardial perfusion and we have the geometry of the plaques, and we do take this into consideration. So clearly there are cases when we have altered the therapy on the basis of VH IVUS.

I still feel that some strategies need to be performed, that is when you randomize people and you make your decision on the basis of VH IVUS or not and look at outcomes. And not necessarily hard endpoints. It could be as simple as the appropriate length of stenting, that kind of stuff.

Q: Or whether to stent or not to stent?
Dr. Voros: Whether to stent or not to stent, that is the ultimate question! We just have to have the natural history trial first before we do the treatment trial -- and the natural history trial is PROSPECT.

Q: Because it's not clear whether stenting a vulnerable plaque before it ruptures is clinically beneficial or not?
Dr. Voros: That's the big question and it is the question today and that's exactly the question that PROSPECT and our ATLANTA study are trying to get at. We have plans, based on our ATLANTA study, that if we reach certain parameters, we would move forward with just that study which is taking hemodynamically non-obstructive lesions, and on the basis of some pre-specified characteristics, based on CT characteristics and VH IVUS characteristics, we would plan to randomize people to stenting vs. no stenting in the non-obstructive lesions. But that's where the frontier is today!

Q: Because there's so much controversy generated, for example, by the COURAGE trial -- does stenting and angioplasty improve outcomes or not?
Dr. Voros: That's right. I think VH IVUS has a huge potential obviously of the intravascular plaque characterization techniques now that are available that are FDA-approved. There are two of them right now, VH IVUS and the near-infrared spectroscopy. Then there’s OCT which is not yet FDA-approved. Of those techniques, quite honestly VH IVUS is the most mature and we collectively have a very extensive experience with that. I think we can start to make some conclusions, but again I think the PROSPECT is critical to have the follow-up data from PROSPECT.

Q: When is PROSPECT data to be released?
Dr. Voros: I think that TCT next year is the plan.

Q: Dr. Voros, thank you for your time.

(More information about VH IVUS can be found at -- a web site from Volcano Corporation.)


This interview was conducted in November 2008 by Burt Cohen of Angioplasty.Org.