The Emperor’s Clothes
In Search of the Vulnerable Plaque
The concepts for pathogenesis of atherothrombosis and the determinants of atherosclerotic plaque stability have evolved rapidly. Heretofore, plaques that appear ulcerative, fissured, and/or thrombotic and that are characterized histologically by a central lipid core, inflammatory infiltrate, and cap thinning have been termed “vulnerable.” Vulnerable plaque has been implicated in the development of unstable angina, myocardial infarction, and sudden cardiac death. However, as emphasized by the consensus opinions of Drs Maseri and Fuster1 and Dr Casscells et al2 expressed in the current issue of Circulation, this popular concept is overly simplistic and inadequate to explain the clinical spectrum of atherothrombotic events. For example, plaque inflammation may be present in patients with chronic stable angina and yet absent in some patients who present with an acute coronary syndrome. Plaque rupture may result in stable, mural endoluminal thrombus and contribute to stepwise, gradual plaque growth, or alternatively may precipitate catastrophic abrupt coronary occlusion. As emphasized by the above-mentioned thought leaders, the concept of vulnerable plaque as the final common pathway by which atherothrombotic events occur ignores the multiple, diverse triggers for acute coronary events, as well as the important contributions of blood rheology and the coagulation cascade (high-risk blood). Important pathophysiological distinctions between structural and functional aspects of plaque vulnerability are outlined by Drs Maseri and Fuster.1
The interplay between anatomic (central lipid core, thin cap) and functional (intrinsic thrombogenicity, intraplaque inflammatory infiltrate) plaque components is further modified by exogenous factors, including mechanical stress, vasomotor tone, intercurrent infections, temperature extremes, blood viscosity, and coagulability. Drs Casscells, Naghavi and Willerson2 further acknowledge the heterogeneity of vulnerable or unstable plaque and extend this concept to the technologies used for its detection. The variable constituents of high-risk plaque will likely require diverse technologies for optimal detection. Thus, a combination of direct measures or indirect markers of inflammatory activity, plaque structural composition, and/or mechanical frailty will likely be complementary.
To facilitate widespread screening of both an intermediate and high-risk patient populations on the basis of currently understood risk predictors, noninvasive imaging techniques will evolve. Techniques currently under development include MRI with gadolinium derivatives or ferrous oxide particles as contrast agents to reflect plaque volume or macrophage density, respectively. Conversely, computed tomographic images with liposomal iohexol to reflect plaque volume or ultrafast/electron beam capability to provide coronary calcium scoring may be useful. Positron emission tomography with 18 fluoro-deoxy glucose may be useful to noninvasively measure plaque burden. Serological evidence from inflammatory markers (interleukins 6 and 18, monocyte chemoattractant protein-1, C-reactive protein), possibly in conjunction with levels of soluble cell adhesive molecules (intracellular adhesion molecule-1, vascular cell adhesion molecule), are likely additional components of the diagnostic armamentarium. The optimal therapeutic approach should incorporate systemically administered therapies because of the multicentric, multivessel proclivity of the disease process. Available therapies recently demonstrated to suppress vascular inflammation include statins, clopidogrel, angiotensin-converting enzyme inhibitors, fibrates, thiazolidinediones, low molecular weight heparins, platelet glycoprotein IIb/IIIa receptor antagonists, and cyclooxygenase 2 inhibitors. In addition, noninvasively detected strategically high-risk zones of vulnerable/unstable plaque may be further selectively treated by invasive/catheter-based strategies, including photodynamic or sonodynamic activation of photosensitizer/sonosensitizer agents that localize within plaque inflammatory/smooth muscle cells or by targeted site-specific drug delivery (needle-based, porous balloon, gel paving).
Novel drug-eluting stent platforms will evolve that do not require stainless steel/metal alloy for radial strength to scaffold these largely noncalcific, noncritical stenoses. Indeed, the traditional high pressure deployment of metallic stents in coronary lesions which have large lipid-pool–like images (characteristic of vulnerable plaque) by intravascular ultrasound has been associated with consequent slow flow (atheroembolism) and protrusion of plaque contents through the stent struts. A biodegradable stent drug delivery platform is intuitively more attractive to allow time-dependent delivery of antiinflammatory and/or antithrombotic medications. The work of Drs Maseri and Fuster1 Casscells et al2 in this issue of Circulation aptly exposes the limitations and inadequacies in the “one shoe” concept of vulnerable plaque that “fits all” aspects for pathogenesis of vascular atherothrombotic events and provides instead, a more dynamic, inclusive frame of reference (Figure) for this process.