Author + information
- Published online March 5, 2018.
- aCVPath Institute, Inc., Gaithersburg, Maryland
- bUniversity of Maryland School of Medicine, Baltimore, Maryland
- ↵∗Address for correspondence:
Dr. Renu Virmani, CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, Maryland 20878.
Plaque rupture is a predominant cause of acute coronary syndromes and sudden coronary death (1). However, not all plaques progress to cause clinical events (2). Many remain dormant for the life of the individual and cause neither symptoms nor clinical events, whereas others progressively narrow but do not rupture, thus resulting in stable angina. However, only a few plaques become progressively unstable in morphology and eventually are the cause of serious clinical events (Figures 1A to 1G). Because we currently lack the understanding and technology to identify correctly which so-called vulnerable plaques (thin-cap fibroatheromas) in the short term will go on to cause symptoms, and especially acute myocardial infarctions, our focus therefore has been on the development of techniques that restore blood flow in arteries possessing hemodynamically significant lesions that cause ischemia or infarction. This reactive strategy has meant that although death rates for heart disease have continued to fall in recent decades, the number of people with cardiovascular disease is rising because many more people are living with the crippling aftereffects of heart attacks (3). In addition to finding better therapies for those patients with heart disease, preventing future events remains a major priority for the cardiology community.
Because most acute coronary syndromes result from plaques that are modest in severity (4,5), coronary angiography is of limited utility in distinguishing lesions with a high short-term risk of causing clinical events. Detailed pathological examination of plaque ruptures has allowed us to define morphological criteria that we believe characterize plaques at high risk for rupture (1). These vulnerable plaques have a large lipid core, a thin fibrous cap, and inflammatory cell infiltration, with calcification resembling plaque rupture lesions but with an intact fibrous cap (1). However, perhaps the greatest problem with this paradigm is that we lack high predictive values for in vivo evidence that these so-called vulnerable plaques actually do go on to rupture. In what was arguably the most thorough attempt to examine the relationship between plaque morphology as identified by intravascular ultrasound (IVUS) and clinical events in living patients, Stone et al. (2) conducted the landmark PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree [NCT00180466]) trial, a study of 697 patients presenting with acute coronary syndromes who underwent 3-vessel coronary angiography and gray-scale and radiofrequency IVUS-virtual histology (IVUS-VH) imaging after percutaneous coronary intervention (2). Subsequent major cardiac events (MACE) over a median of 3.4 years were recorded and adjudicated to be caused either by the original culprit lesion or by untreated nonculprit lesions (2). Although this group was able to define criteria that were associated with new nonculprit MACE (large plaque burden ≥70%, minimum luminal area 4.0 mm2 or less, and the presence of what appeared to be vulnerable plaque characteristics as defined by composition using IVUS-VH), the positive predictive value of these criteria was very low (2). Most patients (88.2%) with lesions consistent with these so-called high-risk characteristics did not have MACE (2). These findings suggested that although such lesion characteristics are conducive to the occurrence of a subsequent event, they are not sufficient to predict which atheromas will undergo plaque progression on a per-patient basis.
In this issue of iJACC, Stone et al. (6) attempt to refine these criteria by adding low endothelial shear stress (ESS) as a potential predictor of nonculprit events in the PROSPECT trial. Using the same dataset but adding ESS values for nonculprit lesions using computational fluid dynamics obtained from angiography and IVUS imaging, the investigators explored whether adding such data would provide additional prognostic information about nonculprit lesions.
Maintenance of physiological laminar shear stress is essential for normal vascular function, which includes the regulation of vascular caliber and the inhibition of proliferation, thrombosis, and inflammation of the vessel wall. Low flow and oscillatory flow are often seen opposite arterial flow dividers that have a predisposition to atherosclerosis. Endothelial cells have different behavioral responses to altered flow patterns that promote atherosclerosis in combination with other well-defined systemic risk factors. Earlier work conducted by Stone et al. (7) in the PREDICTION (Prediction of Progression of Coronary Artery Disease and Clinical Outcome Using Vascular Profiling of Shear Stress and Wall Morphology [NCT01316159]) study demonstrated that the positive predictive value for coronary artery disease progression requiring percutaneous coronary intervention during 1-year follow-up was 22% on the basis of plaque anatomy alone (large plaque burden and small minimal lumen area), but it increased to 41% if low ESS was also present in that plaque. Stone et al. (6) use the PROSPECT trial data to determine the additive value of low ESS in plaque prognostication. By comparing baseline ESS in nonculprit lesions leading to new MACE with randomly selected nonculprit lesions without MACE, a propensity score for ESS was constructed for each lesion, and the relationship between ESS and subsequent nonculprit MACE was examined. Low ESS was strongly associated with MACE (hazard ratio: 4.34; 95% confidence interval: 1.89 to 10.00; p < 0.001). High anatomic risk defined by large plaque burden (≥70%, minimum luminal area 4.0 mm2 or less, the presence of what appeared to be a vulnerable plaque by composition using IVUS-VH) and low ESS were prognostically synergistic: 3-year nonculprit MACE rates were 52.1% versus 14.4% versus 0.0% in lesions with high anatomic risk/low ESS, low anatomic risk/low ESS, and physiological/high ESS, respectively (p < 0.0001). Stone et al. (6) conclude by stating that local ESS provides incremental risk stratification of untreated coronary lesions in high-risk patients beyond their previously defined high-risk plaque criteria.
What, then, are we to make of these data? Does the addition of low-ESS areas provide useful information that could be used clinically to define vulnerable plaques? The study design, in particular, deserves additional comment. The pre-specified comparison between event-causing lesions and non–event-causing lesions makes the results very difficult to interpret on a per-patient basis. Clinically useful information such as positive and negative predictive values could not be reliably assessed because of the small sample size. There were also too few events to allow construction of a comprehensive multivariable model predicting outcomes. Thus the true value of assessing low ESS to predict nonculprit MACE cannot be assessed from these data. What we can say from these data is that they confirm prior observations that lesions with low ESS are generally at higher risk for progression, but it remains unclear how predictive ESS, even when combined with previous measures of high-risk plaque, is for event prediction. In our opinion, it is unlikely that the use of ESS provides significant prognostic value on a per-patient basis, a necessary requirement for prediction of future events with high positive predictive value. Alterations in shear are expected in normal bifurcations, yet not all go on to develop high-risk plaques. Other patient- and lesion-specific factors undoubtedly are important in the development of high-risk lesions.
The larger and perhaps more important question for cardiology is this: “Is the vulnerable plaque paradigm worth pursuing and, if so, how?” Although there have been recent advances in in vivo imaging of coronary plaques with the use of IVUS, optical coherence tomography (OCT), cardiac magnetic resonance, and computed tomography, their resolution is limited, leading to errors in what is being described. We recently evaluated the ability of previously described OCT imaging patterns to describe histological findings reliably in an ex vivo study (8). Most OCT patterns did not correlate with any single histological finding. Previous work has also suggested significant errors in the interpretation of IVUS-VH for describing histological characteristics (9). In the PROSPECT trial only 51% of lesions occurred at sites of vulnerable plaques, whereas other events were associated with thick-cap atheromas. Is this because thick-cap lesions cause events, or is it rather an indicator of how poor IVUS-VH is for identifying high-risk morphological features? One must ask, “Have we been able to locate vulnerable plaques properly using today’s technology?” Pathologically defined criteria such as necrotic core size, extent of macrophage infiltration, and cap thickness are still not able to be assessed reliably using either invasive or noninvasive imaging. Thus we cannot say with certainty that the vulnerable plaque paradigm does not exist.
To explore this issue properly, further investment in technology that is able to assess plaque features with greater accuracy must continue. Recent advances in multimodality imaging such as OCT combined with IVUS or near-infrared imaging may hold significant promise because findings can be confirmed using more than 1 approach (10).
We need tools that can accurately assess the following: the presence of positive remodeling; fibrous cap thickness and its circumferential and longitudinal dimensions; necrotic core size, its location in relation to the lumen, and its eccentricity; the presence of inflammatory cells and whether they are activated; and, above all, the type, thickness, extent, and location of calcium. Beyond these morphological characteristics, we also need additional physiological and biological characteristics (e.g., endothelial shear stress, blood flow patterns, state of endothelial function) and more information about patients themselves, including genetics, as well as biomarkers indicative of systemic inflammation and hypercoagulation. Only by creating a large array of data including an accurate description of coronary plaques in living patients can we properly explore the vulnerable plaque paradigm.
↵∗ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
This study was sponsored by CVPath Institute, a nonprofit organization dedicated to cardiovascular research. CVPath Institute has research grants from Abbott Vascular, Atrium Medical, Boston Scientific, Biosensors International, Cordis–Johnson & Johnson, Medtronic CardioVascular, OrbusNeich Medical, and Terumo Corporation. Dr. Virmani has reported speaking engagements for Merck; has received honoraria from Abbott Vascular, Boston Scientific, Lutonix, Medtronic, and Terumo Corporation; and is a consultant for 480 Biomedical, Abbott Vascular, Medtronic, and W.L. Gore. Dr. Mori has received honoraria from Abbott Vascular Japan, Goodman, and Terumo Corporation. Dr. Finn has sponsored research agreements with Boston Scientific and Medtronic CardioVascular; has served on the advisory board of Medtronic CardioVascular; and has received honoraria from Abbott Vascular, Boston Scientific, and Medtronic. Dr. Torii has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
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