index (LCBI) is the quantification of lipid present in the scanned region and is defined as the fraction of yellow pixels on the chemogram multiplied by 1000. The maximal lipid core burden index (max LCBI) per 4 mm describes the region with the highest lipid burden. ex vivo validation studies support the feasibility of NIRS imaging with reasonable sensitivity and specificity for evaluating the extent of lipidic materials [162, 163]. Signal loss behind calcium due to acoustic shadowing is an important limitation for conventional IVUS, whereas NIRS penetrates effectively through calcium and stents, not affected by lower intensity due to attenuation. Additionally, with inability of IVUS and OCT to visualize or determine actual composition of lipidic plaques due to signal drop‐out, NIRS offers a more reliable and quantitative detection of lipid core plaques than other intravascular imaging methods. On the other hand, a potential limitation of NIRS may be its inability to assess the depth of a lipid core and the measurement of lipid volume.
Figure 1.6 NIRS IVUS imaging of vulnerable plaque. Lipid rich plaque (yellow at left and right images): cross sectional image (left hand) and lon‐gitudinal pullback image with its chemogram (right hand).
Lipid rich plaques
The common denominator for plaque rupture causing ACS is lipid accumulation, either as a lipid core or lipid pools [115]. This has been proved in a study that compared ACS culprit sites with lesions responsible for stable CAD using NIRS [164]. Subsequently, it has been shown that NIRS‐IVUS is highly specific for the identification of ST‐elevation myocardial infarction (STEMI) [165] and non‐ST‐elevation myocardial infarction [166]. According to these studies, a maximum LCBI4mm >400 was the optimal threshold for identification of culprit plaque in patients with both STEMI and non‐STEMI. The visualization of lipid rich plaque on NIRS imaging has been also employed to predict PCI procedural risks and optimize coronary stent implantation. A clinical study examined 62 patients with CAD demonstrated that a maximum LCBI4mm >500 as a discriminatory threshold for the occurrence of periprocedural myocardial infarction after PCI [167]. Moreover, the prognostic value of NIRS‐derived LCBI has been investigated in a study examined 203 patients with CAD [168]. Patients with an LCBI equal to or above the median of 43.0 had a fourfold risk of adverse cardiovascular events during one year follow‐up. Thus, these results indicate the potential of intravascular NIRS imaging for risk stratification of cardiovascular events in patients with CAD. Additionally, the relationship of NIRS‐derived LCBI with cardiovascular disease also indicates the potential benefit of pharmacological lipid rich plaque modulation prior to cardiovascular events. The reduction in yellow plaque by aggressive lipid lowering therapy (YELLOW) trial has demonstrated that short‐term intensive statin therapy reduced lipid content using NIRS in severely obstructive coronary lesions compared with standard therapy [169]. However, in the integrated biomarker and imaging study 3 (IBIS‐3) study, the effect of high intensity Rosuvastatin therapy on coronary plaque composition and LCBI was investigated within non‐stenotic, non‐culprit coronary segments with a relatively low atheroma burden and failed to demonstrate a significant reduction of necrotic core volume or LCBI under high intensity rosuvastatin therapy during one year [170]. Further investigations are required to better understand lipidic materials within vessel wall.
Serum markers correlated to plaque inflammation
Numerous studies have correlated different serologic biomarkers with cardiovascular disease [171–174] leading to a rapid increase in the number of biomarkers available (Table 1.2). These biomarkers are useful in that they can identify a population at risk of an acute ischemic event and detect the presence of so called vulnerable plaques and/or vulnerable patients [175,176]. Ideally, a biomarker must have certain characteristics to be a potential predictor of incident or prevalent vascular disease. Measurements have to be reproducible in multiple independent samples, the method for determination should be standardized, variability controlled, and the sensitivity and specificity should be good. In addition, the biomarker should be independent from other established risk markers, substantively improve the prediction of risk with established risk factors, be associated with cardiovascular events in multiple population cohorts and clinical trials, and the cost of the assays has to be acceptable. Finally, to be clinically useful a biomarker should correctly reflect the underlying biological process associated with plaque burden and progression.
Traditional biomarkers for cardiovascular risk include low‐density lipoprotein (LDL) cholesterol and glucose. However, 50% of heart attacks and strokes occur in individuals that have normal LDL cholesterol, and 20% of major adverse events occur in patients with no accepted risk factors [177]. Therefore, in light of changing atherosclerotic models, vulnerable blood may be better described as blood that has an increased level of activity of plasma determinants of plaque progression and rupture. In the past decade, the potential role of different micro‐RNAs (miRNAs) in the cardiovascular system biomarkers has been widely recognised. Stable extracellular miRNAs circulate in the bloodstream and might serve as novel diagnostic markers for a wide range of cardiovascular diseases and risk factors, such as myocardial infarction [178,179], heart failure [180], coronary atherosclerotic disease [181], hypertension [182], and type 2 diabetes mellitus [183]. It is to be expected that combining multiple miRNAs into a single miRNA profile may provide improved accuracy.
Table 1.2 Serologic markers of vulnerable plaque/patient.
| ReflectingMetabolic and Immune Disorders | ReflectingHypercoagulability | ReflectingComplex Atherosclerotic Plaque |
|---|---|---|
| Abnormal lipoprotein profile (i.e. high LDL, low HDL, lipoprotein [a], etc.)Non specific markers of inflammation (hs‐CRP, CD40L, ICAM‐1, VCAM, leukocytosis and other immuno‐related serologic markers which may not be specific for atherosclerosis and plaque inflammationSerum markers of metabolic syndrome (diabetes or hypertriglyceridemia)Specific markers of immune activation (i.e. anti‐LDL antibody, anti heat shock protein (HSP) antibodyMarkers of lipid peroxidation (i.e. ox‐LDL and ox‐HDL)HomocysteinePAPP‐ACirculating apoptosis markers (i.e. Fas/Fas ligand)ADMA/DDAH (i.e. asymmetric dimethylarginine/dimethylarginine dimethylaminohydrolase)Circulating NEFA (nonesterified fatty acids) | Markers of blood hypercoagulability (i.e. fibrinogen, D‐dimer, factor V of Leiden)Increased platelet activation and aggregation (i.e. gene polymorphism of platelet glycoproteins IIb/IIIa, Ia/IIa, and Ib/IX)Increased coagulation factors (i.e. clotting of factors V, VII, VIII, XIII, von Willebrand factor)Decreased anticoagulation factors (i.e. protein S and C, thrombomodulin, antithrombin III)Decreased endogenous fibrinolysis activity (i.e. reduced tissue plasminogen activator, increased type I plasminogen activator (PAI), PAI polymorphisms)Prothrombin mutation (i.e. G20210A)Thrombogenic factors (i.e. anticardiolipin antibodies, thrombocytosis, sickle cell disease, diabetes, hypercholesterolemia)Transient hypercoagulability (i.e. smoking, dehydration, infection) | Morphology/StructureCap thicknessLipid core sizePercentage stenosisRemodelling (positive vs. negative)Color (yellow, red)Collagen content vs. lipid contentCalcification burden and patternShear stress Activity/functionPlaque inflammation (macrophage density, rate of monocyte and activated T cells infiltration)Endothelial denudation or dysfunction (local nitric oxide production, anti/procoaugulation properties of the endothelium)Plaque oxidative stressSuperficial platelet aggregation and fibrin depositionRate of apoptosis (apoptosis protein markers, microsatellite)Angiogenesis, leaking vasa vasorum, intraplaque haemorrhageMatrix metalloproteinases (MMP‐2, ‐3, ‐9)Microbial antigens (Chlamydia pneumoniae) Temperature Pan Arterial Transcoronary gradient of vulnerability biomarkersTotal calcium burdenTotal coronary vasoreactivityTotal arterial plaque burden (intima media thickness) |
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