Author + information
- Mazen S. Albaghdadi, MD, MS∗ ( and )
- Evan D. Muse, MD, PhD
- ↵∗Division of Cardiology, Northwestern University, 676 North St. Clair Street, Suite 600, Chicago, Illinois 60611
In their recent perspective, Arbab-Zadeh and Fuster explore the generally accepted concept that atherothrombotic events result from the interaction between systemic factors (inflammation and thrombosis) and local substrates (individual plaques). Although this notion has appeared in the literature for more than a decade, the authors emphasize the importance of overall atherosclerotic plaque burden rather than identification and characterization of vulnerable (or high-risk) plaque in cardiovascular (CV) risk prediction.
Fundamentally, the authors accept that “plaque ruptures and erosions are indeed responsible for most culprit lesions in patients with acute events” but express reservations about the feasibility of vulnerable plaque diagnosis, given the prevalence of subclinical plaque rupture events. However, several points are worth considering when evaluating the merits of the authors arguments:
1. Imaging studies associating vulnerable plaque with future CV events have generally not accounted for anatomic plaque burden as a confounder. Similarly, studies of anatomic plaque burden have typically not adjusted for high-risk plaque features. Given this, and that most imaging studies account for similar CV and demographic risk factors, it is instructive to compare the predictive value of selected studies comparing anatomic burden to vulnerable plaque (Table 1). Notably, the adjusted risk estimates for death and/or major adverse cardiac events (MACE) are generally comparable for both plaque burden and plaque vulnerability characteristics. The study by Budoff et al. (1) represents the exception to this trend but was assessed in the extreme upper tier of coronary artery calcium (CAC) (>1,000), constituting <5% of the study population. Importantly, lower CAC in their study was associated with a risk of clinical events comparable to other studies at the same level of CAC.
The studies by Puchner et al. (2) and Criqui et al. (3) (Table 1) are particularly interesting in that they provide insight into the interplay between various prognostic factors in coronary artery disease (CAD): plaque burden and plaque vulnerability. Evaluating patients with chest pain using coronary computed tomography angiography (CTA), Puchner et al. (2) observed that high-risk plaque (defined as at least 1 of the following: positive remodeling, plaque with low Hounsfield units [<30], napkin-ring sign, spotty calcium) was predictive of acute coronary syndromes after adjustment for plaque burden (any coronary artery with a ≥50% or ≥70% stenosis). Criqui et al. (3) found that CV risk was inversely proportional to CAC density (i.e., vulnerable plaque features) at any level of CAC volume (i.e., plaque burden). These studies demonstrate the incremental prognostic value of characterizing features of individual plaque vulnerability in the context of overall plaque burden in CV risk prediction.
2. Intravascular ultrasound (IVUS) has been the predominant invasive imaging modality used to ascertain plaque features. The spatial resolution of IVUS (∼150 μm) is insufficient for the diagnosis of pathological thin-cap fibroatheroma (TCFA; fibrous cap of 65 to 80 μm). Therefore, the limited predictive ability of IVUS to identify TFCAs may have contributed to imprecision in the characterization of lesion morphological changes over time. Virtual histology and integrated backscatter IVUS techniques have been developed to provide additional insight into individual plaque risk stratification by providing information about the spatial distribution of various plaque tissue types (i.e., lipid, fibrous, calcific, etc.). Unfortunately, the spatial resolution of backscatter-based IVUS techniques remains limited, and the ability to accurately distinguish various plaque tissues when compared with real histology is questionable.
3. Most plaque ruptures are subclinical but these events may be a principal mechanism underlying plaque progression and, ultimately, the development of plaque burden. Disregarding rupture-prone plaque risks ignoring the pathophysiological substrate for plaque progression, and ultimately increases in plaque burden.
In conclusion, with the existing, although imperfect, evidence on vulnerable plaque from various clinical studies, there is ample space for debating the predictive value of vulnerable plaque identification. However, promoting the concept of the vulnerable plaque as a myth may hinder further research capable of obtaining novel insights into the transformation of subclinical plaque rupture into manifest atherothrombosis, and limiting the accumulation of knowledge that may shed light on mechanisms of plaque progression. In the absence of evidence, we should not assume evidence of absence in the role of high-risk plaque in the genesis of atherothrombotic events.
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Peter Libby, MD, served as Guest Editor for this paper.
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