of the fibrous cap at the shoulder region has resulted in thrombus formation.
Jaffer et al. have published a detailed review on different techniques for detection of vulnerable plaque based on several biomarkers that have been implemented in recent years [213]. In this context, plaques with active inflammation may be identified directly by extensive macrophage accumulation [214]. Possible intravascular diagnostic techniques [215] based on inflammatory infiltration determination within the plaque include thermography [216] contrast‐enhanced MRI [217] fluorodeoxyglucose positron emission tomography [218] and immunoscintigraphy [219]. In addition, non‐invasive techniques include MRI with superparamagnetic iron oxide [220, 221], and gadolinium fluorine compounds [222, 223].
Biomechanical stress as a trigger for plaque progression and rupture
Despite the exposure of the entire coronary tree to the systemic risk factors and inflammation, spatial distribution of atherosclerotic plaques is often a focal phenomenon [224]. Vascular endothelium is subjected to complex mechanical stresses resulting from its 3‐D geometry, vessel curvatures and cardiac motion. These mechanical strains in combination with fluid frictional forces or shear stress gradients inside the arteries can lead to a number of structural and humoral changes in the endothelial cells [225, 226]. High wall shear stress (WSS) (>15 dyne/cm2) has been found to induce endothelial quiescence and an atheroprotective gene expression profile, whereas low shear stress (<4 dyne/cm2) stimulates an atherogenic phenotype [225]. It has been shown that the plaques and wall thickenings are localized mostly on the outer wall of one or both daughter vessels at bifurcations and along the inner wall of curved segments [224]. In the PREDICTION study, Stone et al. studied the natural history of plaques in 506 patients with ACS treated with percutaneous coronary intervention, and used reconstructed coronary models from angiography and IVUS. 74% patients had follow‐up studies at 6 to 10 months to relate the effects of local haemodynamic milieu on plaque changes. Authors reported that decrease in lumen area was independently predicted by baseline large plaque burden and low endothelial shear stress [227]. Other investigators have reported that high wall shear stress is associated with transformation of plaques into high risk phenotypes prone to instability and rupture [228,229].
Future challenges in the treatment of vulnerable plaques
With the concept of “vulnerable” plaque not nearly as straightforward as once thought, there are challenges to creating a therapeutic strategy for assessing the risk of rupture of vulnerable plaques in asymptomatic patients.
First, there must be an ability to identify the vulnerable plaque with non‐invasive or invasive techniques. It has been demonstrated that coronary plaque composition can be studied with invasive and non‐invasive imaging techniques, allowing real‐time analysis and in‐vivo plaque characterization including the identification of TCFA, however the severity of the inflammatory infiltration of the cap, which certainly plays a major role in plaque disruption, cannot be accurately evaluated even with the most advanced in‐vivo imaging techniques. Moreover, dynamic plaque changes, such as abrupt intra‐plaque haemorrhages from vasa‐vasorum which may be fundamental in predicting the potentiality of a plaque to rupture, will be extremely difficult to identify with real‐time imaging techniques.
A second challenge is that a lesion‐specific approach requires that the number of vulnerable plaques in each patient needs to be known and the number of such lesions need to be limited. That is not the case, however. Several pathological studies indicate the presence of multiple “lipid‐rich” vulnerable plaques in patients dying after ACS or with sudden coronary death [84, 87]. Further complicating the issue: coronary occlusion and myocardial infarction usually evolve from mild to moderate stenosis – 68% of the time, according to an analysis of data from different studies.
The third and fourth challenge is that the natural history of the vulnerable plaque (with respect to incidence of acute events) has to be documented in patients treated with patient‐specific systemic therapy; and the approach has to be proven to significantly reduce the incidence of future events relative to its natural history. At this time, neither is documented nor proved.
Fifth, we believe that at the current stage it is not possible to know which vulnerable plaques will never rupture. Although we suspect it is the vast majority of them, we may have to shift to a more appropriate therapeutic target. In addition, targeting not only the vulnerable plaque but also the vulnerable blood (prone to thrombosis) and/or vulnerable myocardium (prone to life‐threatening arrhythmia) may be also important to reduce the risk of fatal events.
Conclusions
Atherosclerosis is now recognized as a diffuse, and chronic inflammatory disorder involving vascular, metabolic, and immune system with various local and systemic manifestations. A composite vulnerability index score comprising the total burden of atherosclerosis and vulnerable plaques in the coronary, carotid, aorta, and femoral arteries, together with blood vulnerability factors, should be the ideal method of risk stratification. Obviously, such index is hard to achieve with today’s tools. A future challenge is to identify patients at high risk of acute vascular events before clinical syndromes develop. At present, aside from imaging modalities such as IVUS‐ virtual histology, magnetic resonance, and local Raman spectroscopy that could help to identify vulnerable plaques, highly sensitive inflammatory circulating markers such as hsCRP, cytokines, pregnancy‐associated plasma protein‐A, pentraxin‐3, LpPLA2 are currently the best candidates for diffuse active plaque detection. In order to achieve this aim, a coordinate effort is needed to promote the application of the most promising tools and to develop new screening and diagnostic techniques to identify the vulnerable patient.
Interactive multiple choice questions are available for this chapter on www.wiley.com/go/dangas/cardiology
References
1 1 Herrington W, Lacey B, Sherliker P, et al. Epidemiology of Atherosclerosis and the Potential to Reduce the Global Burden of Atherothrombotic Disease. Circ Res. 2016; 118:535–46.
2 2 Pahwa R and Jialal I. Atherosclerosis StatPearls Treasure Island (FL); 2020.
3 3 Wu MY, Li CJ, Hou MF and Chu PY. New Insights into the Role of Inflammation in the Pathogenesis of Atherosclerosis. Int J Mol Sci. 2017; 18.
4 4 Insull W, Jr. The pathology of atherosclerosis: plaque development and plaque responses to medical treatment. Am J Med. 2009; 122:S3–S14.
5 5 Forstermann U, Xia N, Li H. Roles of Vascular Oxidative Stress and Nitric Oxide in the Pathogenesis of Atherosclerosis. Circ Res. 2017; 120:713–735.
6 6 Libby P, Ridker PM, Hansson GK, Leducq Transatlantic Network on A. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009; 54:2129–38.
7 7 Libby P, Buring JE, Badimon L, Atherosclerosis. Nat Rev Dis Primers. 2019; 5:56.
8 8 Gimbrone MA, Jr., Garcia‐Cardena G. Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis. Circ Res. 2016; 118:620–36.
9 9 Ghattas A, Griffiths HR, Devitt A, Monocytes in coronary artery disease and atherosclerosis: where are we now? J Am Coll Cardiol. 2013; 62:1541–51.
10 10 Gimbrone MA, Jr., Garcia‐Cardena G. Vascular endothelium, hemodynamics, and the pathobiology of atherosclerosis. Cardiovasc Pathol. 2013; 22:9–15.
11 11 Davies PF. Flow‐mediated endothelial mechanotransduction. Physiol Rev. 1995; 75:519–60.
12 12 Gimbrone MA, Jr., Topper JN, Nagel T, Anderson KR and Garcia‐Cardena G. Endothelial dysfunction, hemodynamic forces, and atherogenesis. Ann N Y Acad Sci. 2000; 902:230–9; discussion 239–40.
13 13 Pober JS, Cotran RS. The role of endothelial cells in inflammation. Transplantation. 1990; 50:537–44.
14 14 Egan K, FitzGerald GA. Eicosanoids and the vascular endothelium. Handb Exp Pharmacol. 2006:189–211.
15 15 Pober JS, Sessa WC. Evolving