Identification of Vulnerable Plaque — The Quest Continues

The majority of acute coronary syndromes are the result of nonobstructive coronary plaque rupture and subsequent thrombosis. The structure of these plaques, rather than their size, is the major determinant of plaque vulnerability. Identifying vulnerable from stable plaque remains an elusive goal, but one which could have a significant impact on the primary prevention of myocardial infarction in the future. In a recent editorial in the New York Times, this concept of identifying which patients are prone to plaque rupture was described as the “Holy Grail of cardiology”.¹ In recent years, a number of invasive modalities have been developed to interrogate plaque stability, although no single method is superior in identifying all the main characteristics of plaque vulnerability. There are four principal features of presumed plaque vulnerability, namely, a thin fibrous cap (2 Diagnostic coronary angiography is effective in identifying obstructive lesions, however, angiography gives a two-dimensional representation of the coronary artery lumen and provides no information on the vessel wall. For this reason, specific features of plaque composition are not visualized by this method. Intravascular thermography has been used by some investigators to identify potentially vulnerable plaque. Increased macrophage activity within the lipid core and the fibrous cap may be an important predisposing feature of plaque vulnerability and impending rupture. These inflammatory cells are metabolically active and increase temperature locally. Thermography relies on temperature heterogeneity along the vessel wall to identify vulnerable plaque, where there is increased heat production from inflammatory cells. An accurate correlation between thermal heterogeneity and plaque inflammation has been demonstrated in ex vivo models using the carotid artery and in vivo as well.^3,4 Several different catheter-based techniques have been designed to measure temperature along the artery wall including basket catheter technology (Volcano Therapeutics, California), a catheter-based system that involves expanding nitinol strips with thermistors at the distal end (Thermocore Medical Systems NV, Merlbeke, Belgium), and catheter-based infrared thermography to map temperature differences along the vessel wall.⁵ A significant limitation of these catheter-based thermography devices is the inevitable interruption to coronary blood flow and the resultant effect on thermal heterogeneity. An alternative approach to intravascular thermography, described in this issue by Wainstein et al, overcomes the problem of impaired coronary blood flow by utilizing a guidewire-based system.⁶ If thermography is to have a practical future, a guidewire-based approach makes it much more user-friendly. The obvious limitations of intravascular thermography by any means in analyzing individual plaque stability are that it gives no direct indication of the size of the lipid pool, thickness of the fibrous cap or the degree of positive remodeling. In addition, it is essential for accurate assessment of thermal heterogeneity that the thermistor be in direct contact with the vessel wall, potentially predisposing to the risk of endothelial disruption. In terms of the validity of this technique, previous ex vivo animal studies have demonstrated a correlation between temperature at the arterial wall involving plaque and total macrophage count at that specific location. Human studies involving intravascular thermography and directional atherectomy samples have shown an association between thermal heterogeneity and histological inflammation, with higher temperature readings from areas with plaque and higher macrophage infiltration.^7–9 Clinical studies have also shown greater thermal heterogeneity from culprit lesions in patients with acute coronary syndromes than from lesions in patients with stable angina.¹⁰ In the current provocative study, there is corroborative evidence suggesting an association between thermal heterogeneity and histological and intravascular ultrasound (IVUS) data supporting plaque vulnerability. It is also quite interesting that thermal heterogeneity was noted in the one case of subsequent stent thrombosis.⁶ However this analysis and many others have been relatively small observational studies. Additionally, discrepancies between ex vivo and in vivo temperature measurements suggest there may be a cooling effect of coronary blood flow, which does raise concern over the accuracy of this technique in vivo.^3,11–14 Another potential limitation of intravascular thermography, or any invasive means of identifying vulnerable plaque, is that coronary atherosclerosis is diffuse and not a focal pathology. The inflammatory process is not restricted to a culprit lesion, particularly in patients with acute coronary syndromes. Postmortem studies have confirmed widespread inflammation in the coronary tree not confined to the culprit plaque.¹⁵ Furthermore, plaque vulnerability may be a dynamic process, both temporally and spatially; thus, identification of a vulnerable plaque in a particular coronary segment today may not mean as much if that same plaque is not deemed vulnerable in a few months. Greyscale IVUS is the most commonly used modality for assessing plaque size, morphology and progression with time. The lipid-rich core is echolucent and the other structures comprising plaque have differing degrees of echodensity. This modality is imprecise and its resolution is limited to 100–200 µm, preventing the accurate assessment of the thickness of the fibrous cap. Prospective studies have failed to identify plaques at risk of future rupture. There are a number of adjuvant modalities that can be used with IVUS to aid in the detection of plaque vulnerability. IVUS elastography and palpography work on the principle that soft, lipid-rich plaque distends more in response to increases in intra-arterial pressure during systole than hard, fibrocalcified, stable plaque. Using this technique, soft-tissue vulnerable plaque has been detected in postmortem coronary arteries with a high degree of sensitivity and specificity.¹⁶ Another potentially useful modality of IVUS is virtual histology (VH), which relies on spectral analysis of radiofrequency data to divide plaque into four specific histological subtypes (calcified, fibrous, fibro-lipidic and lipid-rich) which are color-coded (Figure 1). IVUS-VH offers assessment of plaque size and tissue composition, except regarding the thickness of the fibrous cap. Theoretically, combining several modalities such as IVUS-VH, elastography and thermography might provide complementary information regarding plaque vulnerability. Optical coherence tomography (OCT) allows high-resolution (up to 15 µm), real-time imaging of the arterial wall by emitting light with a wavelength close to the infrared range which is reflected to differing degrees by the tissue components comprising the plaque. The validity of this modality has been confirmed in animal models, which have yielded a close correlation between live OCT data and histology once the animals have been sacrificed.^17,18 Its high-resolution imaging enables the thickness of the fibrous cap to be assessed, but the main drawback of this modality is that OCT must be performed in a bloodless field, requiring temporary occlusion of the artery proximally. Angioscopy enables direct visualization of the arterial wall. Again, it must be performed in a bloodless field, and provides no information on the thickness of the fibrous cap, the size of the lipid core, or the degree of positive remodeling. Nevertheless, the observation of yellow plaque has been shown to be accurate for the identification of vulnerable plaque.¹⁹ Finally, intravascular magnetic resonance imaging (MRI) is effective, particularly for visualizing the lipid core within plaque. It uses a separate MRI probe which can be passed down the artery of interest. Ex vivo coronary and aortic studies have demonstrated a good correlation between intravascular MRI findings and histology results.^20,21 While invasive modalities to assess plaque vulnerability may have theoretical use in patients already undergoing catheterization, for widespread screening, a noninvasive imaging modality or a panel of biomarkers may ultimately prove to be more acceptable. In summary, no single invasive modality is yet ideal for interrogating all four main characteristics of plaque vulnerability. There remains doubt whether any of these invasive strategies can predict future acute coronary events for the individual plaque in question, and ongoing and future clinical trials will need to address this crucial point. Until then, the quest for a rigorous diagnostic test for predicting plaque vulnerability continues.

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