Whereas stabilized atherosclerotic lesions progress slowly, vulnerable plaques suddenly rupture and cause thrombosis, resulting in acute coronary syndrome (ACS). Vulnerable plaques can be clinically identified by intracoronary imaging modalities such as intravascular ultrasonography (IVUS) or optical coherence tomography (OCT) and are known to have the imaging features of thin-cap fibroatheromas (TCFAs). However, in recent clinical studies, the identification of vulnerable plaques by IVUS failed to improve the predictability of cardiovascular risk when compared to existing models.1)2) In some interesting studies, only a small number of vulnerable plaques actually ruptured, and most vulnerable plaques showed a silent clinical course even if they were ruptured.3) Therefore, the concept of vulnerable plaques has recently been challenged and requires further perspectives to be identified.4)5) Some new factors are proposed to distinguish the “real vulnerable plaque” that consequently develops into clinical events and to define “vulnerable patients”.6) Morphological and physiological factors, such as microcalcification, cholesterol crystals, the apoptosis of macrophages and endothelial shear stress (ESS), seem to play an important role in causing the instability of plaques and the inflammation of local atherosclerosis.7)8)9)10) Here, we summarize the characteristics of vulnerable plaques and review the latest pathological and physiological mechanisms of plaque formation and rupture.

Historically, since the first report by autopsy data in 1844, the main cause of acute myocardial infarction (MI) has been known as plaque rupture accompanied by superimposed coronary artery thrombosis.11) Afterwards, thrombosis caused by fissures and erosions in the intimal surface of coronary arteries was reported.12)13) The authors introduced the term “intramural atheromatous abscess” and reported the existence of a necrotic material accompanied by a thrombus. Davies14) demonstrated the role of the inflammatory mechanism associated with the progression of plaque instability and the pattern of plaque disruption. In 1989, the nomenclature of the vulnerable plaque was adopted by James E. Muller et al., and the importance of identifying high-risk lesions amenable to treatment was raised in 2003.15)16) The concept of a TCFA, a major precursor of ACS, was presented as a rupture-prone plaque with a thin fibrous cap (<65 µm thick) accompanied by an infiltration of many inflammatory cells and a few smooth muscle cells, a large necrotic core, spotty calcification and positive outward remodeling.17)18)

Although molecular imaging technology in small animals, including fluorescence imaging, bioluminescence imaging, ultrasound, micro-PET, micro-single photon emission CT, micro- CT, and high-field small-animal magnetic resonance imaging (MRI), has tremendously advanced, imaging molecular signals in human coronary plaques is still not easy. We can expect the development of an atherosclerotic molecular imaging field if human imaging platforms or probes make rapid progress.30)31) Many researchers have studied the applicability of molecular MRI to detect macrophage activity, apoptosis, and adhesion molecules in plaques using gadolinium chelates or iron oxide nanoparticles.32) Whereas MRI is suitable for fast-moving coronary arteries due to its high spatial and time resolution, it has lower imaging sensitivity, which requires a large amount of potentially toxic imaging agents for molecular imaging.33) Thus, an imaging platform using PET and its probe is highly anticipated for the introduction of the molecular imaging of vulnerable plaques in the clinics (Figure 2). The identification of an asymptomatic vulnerable plaque before it ruptures and its treatment with aggressive and/or advanced medical therapy with or without revascularization is an unmet clinical need in interventional cardiology.

The concept of a TCFA as a vulnerable plaque has been challenged lately because very few TCFAs cause ACS.34) The natural history of TCFAs varies and, in most cases, has an indolent course transforming into a more stable plaque.35) Moreover, asymptomatic plaque rupture may also occur in the condition of less severe stenosis or less thrombus formation. Abrupt vessel occlusion accompanying thrombus by rupture was more likely to occur in severe stenoses and in the condition of a “vulnerable patient”. The concept of a “vulnerable patient” requires altered coagulation or thrombosis, endothelial dysfunction, and hemodynamic factors.36) Recently, introduced intravascular imaging techniques, such as IVUS and OCT, help to see the characteristics of lesions in detail, but this imaging-guided approach failed to improve clinical outcome. Currently, fractional flow reserve (FFR) is the most powerful tool in assessing the potential ischemic risk of lesions and in reducing future clinical events in patients with symptoms.

Recently, there have been efforts to explain the mechanism of plaque rupture by hemodynamic and physiological factors, such as shear stress and fluid dynamics. The ESS resulting from friction on the surface of the endothelium is closely related to the pathogenesis of atherosclerosis, plaque formation, and the progression of plaque vulnerability. It has been reported that low ESS is a powerful stimulus that precedes atherosclerosis by inducing lipid aggregation, neovascularization and expanding plaque volumes in previous pig and human data.37)38)39) In addition, the low ESS increases the activity of the major elastolytic matrix metallopeptidases (MMPs) and cathepsins. It also affects endogenous inhibitors such as tissue inhibitors of metalloproteinases and cystatin C, resulting in the fragmentation of the internal elastic lamina.37) Low ESS causes inflammatory cells to migrate to the media, resulting in the degradation of the matrix and vessel remodeling. Furthermore, the low ESS increases the activity of collagenolytic MMPs, resulting in the degradation of collagen and the thinning of the fibrous cap.38)39) Recent clinical studies with IVUS and OCT demonstrated that low ESS is an independent predictor of plaque progression and expansive remodeling with lumen narrowing.40)41) The ESS is associated with plaque rupture as well as the production of atherosclerotic plaques.42) Stenotic vulnerable plaques create a heterogeneous local ESS environment, such as low ESS in the upstream shoulder, high ESS in the neck, and low ESS or oscillatory stress in the downstream shoulder of plaques.43) The majority of ruptures occur on the upstream side of the plaques and result from low ESS and high local wall stress.44) Rupture can also occur when very fast blood flow and high ESS are accompanied by the maximal stenotic lesions. A very recent study investigated the prognostic value of the ESS measure in the upstream shoulder to predict MI in 441 patients who were deferred with FFR≤0.80.45) Higher ESS in the proximal segments of stenotic lesions was predictive of MI and had incremental prognostic value in addition to the FFR value.

Plaque vulnerability and plaque rupture develop from a complex interplay of anatomical and hemodynamical factors. The identification of TCFAs by imaging modality; the imaging detection of molecular signals in plaques including microcalcification, apoptosis, inflammation, and/or angiogenesis; and the hemodynamic assessment of ESS and local wall stress by computational fluid dynamics all contribute to the better identification of plaque vulnerability, resulting in a better clinical outcome by adopting state-of-the-art therapeutics and selective coronary interventions.