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Detecting Vulnerable Plaque

Cath Lab Digest talks with Simon R. Dixon, MBChB, FACC, FRACP, Director of the Cardiac Catheterization Laboratory and the Co-Director of Cardiovascular Research at William Beaumont Hospital in Royal Oak, Michigan.
Cath Lab Digest talks with Simon R. Dixon, MBChB, FACC, FRACP, Director of the Cardiac Catheterization Laboratory and the Co-Director of Cardiovascular Research at William Beaumont Hospital in Royal Oak, Michigan.
How is a vulnerable plaque clinically defined? Coronary plaque rupture with superimposed thrombus is the proximate cause of acute coronary syndromes (ACS). “Vulnerable plaque” is the atherosclerotic lesion defined as the precursor to coronary plaque rupture. A frankly unstable, disrupted atherosclerotic plaque is characterized pathologically as an inflamed, thin-capped fibroatheroma (TCFA). Thrombus forms upon this disrupted plaque, leading to an abrupt reduction in coronary blood flow, clinically manifested as ACS, with the patient presenting with chest pain or other symptoms, EKG changes and often enzymatic biomarkers indicative of myocardial necrosis. In some cases, these disrupted plaques present as sudden cardiac death due to lethal arrhythmias. A key question is whether there are precursor stable, but “vulnerable,” plaques that transition to unstable lesions, which might be detectable prior to disruption with therapies designed to prevent ACS and sudden death. The concept of vulnerable plaque was first described by Dr. James E. Muller over 20 years ago, based on observations in studies of patients with acute myocardial infarction (MI), in whom he noted that these acute vascular events tended to occur most commonly early in the morning. He hypothesized that these event clusters must represent patients with “vulnerable plaques” that had become disrupted in response to some circadian early morning trigger. The trigger induced an abrupt transition from a lesion that was stable but vulnerable, to a frankly disrupted, thrombotic and clinically unstable culprit. His seminal work serves as the basis for our present concept that unstable plaques develop in “vulnerable patients” i.e. those who are at greatest risk of developing vulnerable lesions. A variety of technologies, both invasive and non-invasive, have been developed to try to characterize vulnerable plaques. Extensive work has also been done to delineate clinical characteristics that identify “vulnerable patients.” Abundant pathological and intravascular ultrasound (IVUS) data is now available to support the existence of one or more distinct plaque entities that fulfill the criteria of a “vulnerable plaque.” Based on these studies, TCFAs appear to be at least one common precursor to disrupted plaque. As a result, a variety of technologies, both invasive and non-invasive, have been developed to try to detect TCFAs in patients before they actually rupture and become clinically unstable. An appreciation of the information necessary to precisely characterize plaques is essential. The ideal tool would provide a complete roadmap of atherosclerotic burden throughout the coronary tree and provide data characterizing the architecture, composition and dynamic biology of each lesion. Comprehensive plaque analysis should optimally include the following parameters: 1) Architecture: plaque volume, length, eccentricity, remodeling and impact on lumen area; 2) Physiology: impact on coronary flow reserve; 3) Composition: lipid, fibrous tissue, calcium, etc; and 4) Patho-biology: presence of inflammation, neovascularization, fibrous cap metabolism, apoptosis, etc. Presently available and emerging technologies to detect vulnerable plaque include traditional grayscale IVUS, IVUS Virtual Histology (Volcano Therapeutics), optical coherence tomography (OCT) and near infra-red (NIR) spectroscopy the (LipiScan catheter, InfraReDx, Inc). These devices provide either structural or biochemical data that help characterize the architecture and biologic activity of atherosclerotic plaque. Each technology has strengths and limitations. What role does inflammation play? Unstable plaque has a fibrous cap that “walls off” the lipid core of the plaque, which serves as a barrier, preventing the blood flowing through the lumen from meeting the thrombogenic lipid core. In patients with ACS, the fibrous cap becomes inflamed, thins and ruptures, exposing the clot-prone intraplaque “gruel” to clotting elements within luminal blood and thereby resulting in coronary thrombosis. Thus, inflammation appears to play a role locally at the point of plaque rupture. Inflammation appears to be a pan-coronary process, resulting in “multifocal” patterns of plaque instability and vulnerability. Angiographic observations demonstrate that nearly 50% of patients with acute MI manifest multiple sites of plaque instability. IVUS, angioscopic and pathological studies have confirmed that ACS patients harbor multiple sites of plaque rupture and, importantly, multiple TCFAs as well. It is important to note that inflammation exists not only locally within the coronary bed, but appears to be systemic. Patients with ACS typically show evidence of systemic inflammation, as indicated by elevated biomarkers such as C-reactive protein (CRP). Exactly what triggers inflammation in the systemic circulation and how it may impact the coronary circulation to induce plaque vulnerability and frank instability has been the subject of many hypotheses and intense scientific investigation. The answers are not yet fully known, and no “smoking gun” absolutely proves that systemic inflammation causes plaque rupture, although that is the suspicion. Do we know if plaques like TCFAs are an early version of what later becomes hard, calcified plaque — or are there simply different types of plaque? Atherosclerosis is a chronic disease punctuated by acute flares, some of which are clinically manifest as ACS, others of which occur “silently.” Thus, atherosclerosis progresses in an indolent pattern with some staccato bumps over decades. Plaques have various chemical and cellular constituents. Earlier stage lesions tend to be lipid-laden, then, as they advance, may contain variable volumes of lipid, fibrous tissue and cells (inflammatory and smooth muscle). Plaques may have a thin fibrous cap or a thick fibrous cap. Calcification tends to be a later stage in the process, but there is wide variation in composition from plaque to plaque, even within a single patient, i.e. patients may have plaques that are fibro-calcific as well as lipid-rich. They may have plaques that are TCFAs, and they may have plaques that are inflamed and ruptured. There are also transitions in the life of a plaque, in which it becomes eroded or frankly disrupted over time; intra-plaque hemorrhage is also an important pathophysiological process that contributes to plaque progression, instability and possibly calcification. To simplify, the TCFA can be viewed as an earlier stage of the plaque, whereas the fibro-calcific lesion is a more chronic scarred-down spectrum of the process. You are seeking out potentially vulnerable plaques with the LipiScan catheter, which provides what is called an intravascular chemogram. What does it tell us? The near-infrared LipiScan catheter uses the basic principle of spectroscopy, a technique employed by chemists to identify molecules based on their distinct spectroscopic signature. InfraRedx took this principle and created a catheter with a laser emitting a specific wavelength of light trained at linoleic acid, the major chemical constituent of cholesterol within plaques. The laser is built into a catheter that performs analogous to an IVUS catheter: it goes over a coronary wire just like an IVUS catheter. An automatic pullback device pulls the infrared catheter back within the artery from distal to proximal. As the catheter is being pulled back, the optical tip scans circumferentially, like a searchlight, around the vessel. A spectrum of light goes through the blood and into the vessel wall, and is reflected back. What is contained in the wall absorbs some of the spectra. The spectroscopic signature is a function of the light sent out and the light received, and that light which doesn’t come back (is absorbed), becomes the signature of the chemical constituent — in this case, a lipid. This technique provides a “chemographic” map of cholesterol deposits within the artery, displayed as if the artery had been laid open and spread out from distal to proximal. The “chemogram” is based on an algorithm that quantitates the likelihood of a lipid-core plaque in any particular 2 mm block of vessel. The chemogram is color-coded, with bright yellow indicating a greater than 90% likelihood of a lipid-core plaque and red indicating no evidence of a lipid-core plaque. The chemogram approach was validated in an autopsy study (published in the Journal of the American College of Cardiology), which showed that this technique was highly accurate, specific and appropriately sensitive in detecting lipid-core plaque as correlated with histopathologic confirmation of lipid-core plaques. The FDA, after reviewing that data, gave approval for the LipiScan catheter for the detection of lipid core plaques of interest. Can you tell us about the SPECTACL trial? The SPECTroscopic Assessment of Coronary Lipid (SPECTACL) trial was the first-in-human study of the InfraRedx near-infrared (NIR) LipiScan catheter. The design involved patients undergoing angiography, who then underwent IVUS as well as a LipiScan of the vessel. The primary goal of the trial was to determine whether the signals obtained in patients were spectrally similar to those obtained in autopsy studies with clear pathologic validation that the lipid signals were in fact coming from lipid-rich plaques. The results of the SPECTACL trial, which have been presented in abstract form and are now submitted for publication in a peer-review journal, showed that the signals obtained in patients were spectrally similar to those obtained in the autopsy-validated lesions. How does the LipiScan catheter compare with angiography, intravascular ultrasound, optical coherence tomography and magnetic resonance imaging? The techniques are very different, but complementary. Selective coronary angiography is the “gold standard” for detection of atherosclerosis and quantitation of the magnitude of obstructive disease. Unfortunately, angiography has intrinsic limitations. It provides a two-dimensional “lumenogram” that at best delineates the effects of plaque in the vessel wall that encroaches upon the lumen. While these images delineate the gross presence of disease and can quantify percent stenosis, angiography consistently underestimates the magnitude of atherosclerotic burden, particularly in earlier-stage disease, where positive vascular remodeling may allow “normal” lumen caliber despite substantial vascular wall plaque. Angiography is very accurate in the detection of complex, unstable plaques in patients with ACS. Unfortunately, angiography fails to detect the many plaques with subtler but pathologically manifest ulceration and rupture. It reflects only a subset of truly unstable coronary lesions and offers virtually no insight regarding the many vulnerable but not yet ruptured plaques that serve as the substrate for subsequent coronary events. Angiographic confirmation of complex plaque undoubtedly represents only the “tip of the iceberg” of plaque instability and vulnerability. Intravascular ultrasound provides direct architectural data on intramural plaque as well as its effect on the lumen. It provides a beautiful picture with regard to not only the degree of luminal narrowing and percent stenosis, but also the specific area of lumen compromise. IVUS provides information about plaque architecture, specifically, the degree of eccentricity and the pattern of remodeling, both of which are important features which may predict plaque vulnerability. There is some data suggesting that vulnerable plaques tend to be bulky, eccentric and positively remodeled, whereas more stable plaques are concentric and negatively remodeled, but this has yet to be firmly established. Intravascular ultrasound is also very good at detecting disrupted plaques, delineating ulceration, fissuring, dissection and thrombus. The LipiScan catheter provides a completely different set of data regarding the chemical composition of the plaque in the wall, showing to what degree it is comprised of a lipid core. Virtual Histology also has capabilities to delineate plaque composition, employing integrated backscatter ultrasound analysis to differentiate lipid versus fibrotic plaque. Optical coherence tomography (OCT), a light-based technique, has great promise for plaque characterization. Similar to IVUS in its over-the-wire deployment, OCT provides breathtaking images of plaque architecture, including fibrous cap thickness and whether or not the cap is disrupted. OCT also has promise for detecting lipid composition and also may be able to delineate inflammation within plaque. There are some early studies looking at magnetic resonance imaging (MRI) on a catheter to characterize plaques, but this work is not quite as advanced as the other techniques. Any contraindications for use of the LipiScan catheter? The risks and limitations of the LipiScan catheter are similar to the IVUS catheter. Can you share more about the work going on at Beaumont Hospital? We were involved in the SPECTACL trial and have been using the catheter in patients since its approval by the FDA in May 2008. Cardiologists at Beaumont have found the LipiScan device provides valuable data in several situations, most particularly in vessels with diffuse coronary disease that are undergoing stenting. Daily, interventional cardiologists must make decisions regarding the length of vessel to stent in these types of patients. In patients with a discrete, severely stenotic zone with contiguous but milder disease (often throughout the vessel), the question is whether to “spot stent” only the most critical narrowing, or cover contiguous milder disease which may result in an extensive length of vessel treated, usually requiring multiple stents. Importantly, the angiogram alone typically underestimates the extent of atherosclerosis, often labeling as “mild” substantial, bulky, positively remodeled plaques. Implanting a stent that leaves uncovered adjacent zones containing bulky, lipid-laden plaques has been associated with potential problems, including sub-acute thrombosis, restenosis or plaque progression that may be a source of future chronic or acute ischemic events. These considerations are intensified in patients with ACS, who are known to harbor multi-focal plaque instability, multiple TCFAs and often have diffuse coronary inflammation. The LipiScan catheter provides data that may help inform and refine decisions in such diffusely diseased vessels. In our early clinical experience, in cases with focal severe stenoses and angiographically “mild” contiguous disease, when the Lipiscan chemogram indicates these neighboring zones contain lipid-core plaque, operators have, in some cases, chosen to cover these contiguous areas during stenting. Conversely, if such milder disease segments were not lipid-laden (presumably more fibrous), such data have led to an approach of limited “spot stenting.” Knowledge of the extent of regional lipid-core plaque has also helped in avoiding stenting of milder segments which might have led to “jailing” of side branches. However, it is important to emphasize that the optimal approach to such patients has not yet been delineated and how best to apply the chemogram data clinically will require substantial research. In the meantime, we are faced with and must make such decisions every day in the patients we presently treat. Cardiologsts at Beaumont have been using data provided by the LipiScan catheter, typically in combination with IVUS and angiography, to provide more comprehensive data on the extent, severity and composition of plaque, which in aggregate may inform and refine decisions in patients. That scenario brings to mind the utilization of fractional flow reserve (FFR). Is it correct that the LipiScan catheter provides information about the plaque chemical composition, whereas FFR provides physiological information regarding the impact of any given narrowing on blood flow? That statement is correct. It’s very important to distinguish that the degree of narrowing in the vessel by angiography and delineation of chemical constituents by LipiScan do not necessarily determine whether a particular narrowing is limiting coronary blood flow. With a very severe angiographic stenosis of greater than 75 or 80% narrowing, one can be reasonably confident that the lesion will indeed be flow-limiting. If there is less than 30 or 40% narrowing, one can be relatively confident that the lesion is not flow-limiting, although it could still be bulky, lipid-laden, inflamed and a vulnerable plaque that could cause problems. In contrast, angiography has significant limitations in predicting the physiological significance of narrowings in the range of 40-75%. In such cases, particularly if non-invasive stress testing data is lacking or inconclusive, the FFR technique is now the gold standard to measure coronary blood flow reserve and therefore lesion significance. What are your plans for the future? There are quite a few studies planned from Beaumont. We hope to be able to shed further light on the use of this technique in various kinds of patients going forward. Dr. Dixon can be contacted at sdixon@beaumont.edu
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