Summary of different spectroscopic methods.
Acute coronary syndrome (ACS) arising from plaque rupture is the leading cause of mortality worldwide. Near-infrared spectroscopy (NIRS) combined with intravascular ultrasound (NIRS-IVUS) is a novel catheter-based intravascular imaging modality that provides a chemogram of the coronary artery wall, which enables the detection of lipid core and specific quantification of lipid accumulation measured as the lipid-core burden index (LCBI) in patients undergoing coronary angiography. Recent studies have shown that NIRS-IVUS can identify vulnerable plaques and vulnerable patients associated with increased risk of adverse cardiovascular events, whereas an increased coronary plaque LCBI may predict a higher risk of future cardiovascular events and periprocedural events. NIRS is a promising tool for the detection of vulnerable plaques in CAD patients, PCI-guidance procedures, and assessment of lipid-lowering therapies. Previous trials have evaluated the impact of statin therapy on coronary NIRS defined lipid cores, whereas NIRS could further be used as a surrogate end point of future ACS in phase II clinical trials evaluating novel anti-atheromatous drug therapies. Multiple ongoing studies address the different potential clinical applications of NIRS-IVUS imaging as a valuable tool for coronary plaque characterization and predictor of future coronary events in CAD patients.
- near-infrared spectroscopy (NIRS)
- intravascular ultrasound (IVUS)
- thin-cap fibroatheroma (TCFA)
- acute coronary syndrome (ACS)
- vulnerable plaque
Coronary artery disease (CAD) is the leading cause of global mortality and the rupture of an unstable atherosclerotic plaque precedes the majority of acute coronary syndromes (ACS) [1, 2]. Autopsy studies have shown that the putative substrate for most ACS and many cases of sudden cardiac death (SCD) is the rupture of a thin-cap fibroatheroma (TCFA), the so-called “
Near-infrared spectroscopy (NIRS) is a novel intravascular-imaging modality that provides chemical assessment related to the presence of cholesterol esters in lipid cores and can generate spectra that distinguishes cholesterol from collagen in coronary plaques through their unique spectroscopic fingerprints . NIRS was first used in 1993 for the detection of lipid content in an experimental animal model , followed by subsequent
2. Near-infrared spectroscopy system
2.1. Principles of diffuse reflectance NIRS
Spectroscopy is based on the analysis of electromagnetic spectra induced by near-infrared light and provides direct evaluation of plaque composition, which could yield information on plaque vulnerability . Several spectroscopic methods have been investigated for the purpose of identifying atherosclerotic plaque composition, although the commercially available catheter uses diffuse reflectance NIRS [13, 25]. The principle of NIRS relies on the interaction of light in the form of photons with different functional groups of organic molecules in a tissue, which results in reflected light in the NIR region from molecular vibrational energy in the form of oscillations of atoms within their chemical bonds. Photons can be absorbed or scattered by tissue, which determines the amount of light that is detected by the spectrometer. The wavelengths of light in NIRS are approximately in the 800–2500 nm range. Unique combinations of carbon-hydrogen (C-H), nitrogen-hydrogen (N-H), and oxygen-hydrogen (O-H) bonds are responsible for the major absorption of NIR light, whereas each functional group of large complex molecules yields absorption patterns at specific wavelengths, known as the
Diffuse reflectance NIR spectroscopy has many features that enable
|Raman NIRS||Fluorescence spectroscopy||Diffuse reflectance NIRS||Nuclear magnetic resonance (NMR) spectroscopy|
|Principle||Raman shift from the scattering of a photon upon interaction with matter, generating a near-infrared wavelength forming the Raman spectra||Absorbance of energy from a tissue exposed to ultraviolet light, which in turns releases energy in the form of light||Reflected light from a tissue detected by the spectrometer at a wavelength, generating a NIR spectrum||Chemical shift from chemical groups exposed to an oscillating electromagnetic field and frequencies decoded by the Fourier transform to generate NMR spectrum|
|Plaque characterization||Cholesterol esters, collagen, phospholipids, triglycerides, calcium||Collagen, elastin fibers, lipoproteins, calcium, macrophages, foam cells||Lipid-core plaques||Unsaturated and polyunsaturated fatty acids, cholesterol esters, phospholipids, triglycerides|
|Validation studies||13-Carbon NMR used in |
|Advantages||Evaluates the chemical composition of living tissues|
Signal more specific but weaker than diffuse reflectance NIRS (difficult to detect signal
|Strong fluorescence in arterial tissue, enabling rapid time acquisitions||Evaluates the chemical composition of living tissues, NIR light can penetrate blood and acquire signals from structures several millimeters deep relative to tissue surface||Lack of ionizing radiation (less radioactivity with carbon-13), noninvasive modality, enables to study several biological processes with metabolic, physiologic, and anatomic data combined to imaging|
|Availability||In development—fiber optics catheter-based system for PCI applications under investigation||No ||Catheter-based NIRS-IVUS system used as a clinical application||Costly, preclinical research|
2.2. NIRS-IVUS-combined catheter system
Spectroscopy has a strong fundamental basis for compositional measurement and is a highly efficient method for the identification of chemical components of unknown organic molecules. A single NIRS modality catheter system, the LipiscanTM (InfraRedx Inc., Burlington, MA, USA), was first developed for invasive detection of LCP . In order to obtain anatomical information on the vessel and optimal plaque characterization, a hybrid technology (TVC Imaging SystemTM, InfraRedx Inc.) combining near-infrared spectroscopy(NIRS) and intravascular imaging (IVUS) was further developed, which allows simultaneous, co-registered acquisition of structural and compositional data of coronary artery plaques. Thus, combining the two complementary technologies enables a complete assessment of patient’s arteries, including vessel size and structure, plaque volume, area, and composition [26, 35].
The commercially available NIRS-IVUS imaging system consists of a 3.2-French (F) rapid-exchange catheter compatible with 6F-guiding catheters, a pullback and rotation device, and a console that houses the scanning NIR laser, the computer that processes the spectral signal and two monitors [10, 26, 36]. Within the catheter body is a rotating core of optical fibers that deliver near-infrared light and measure the proportion of light reflected back over the range of optical wavelength (800–2500 nm) in the form of an imaging spectrum. The catheter-imaging core enables to collect data rapidly by rotating at 960 rpm with synchronized pullback at an automated speed of 0.5 mm/s. The system acquires >30,000 spectra per 100 mm. IVUS images are simultaneously acquired by a transducer at a frequency of 40 MHz and with an axial resolution of 100 μm, together with co-registered NIRS measurements, with a maximum imaging length of 12 cm and a depth of 1 mm or less. Thus, the NIRS spectra data are mapped and paired with corresponding cross-sectional IVUS frames, presented as a ring around the IVUS image [26, 27, 35, 36]. An upgrade version of the TVC catheter Imaging SystemTM was released by the company in 2015, which uses an extended bandwidth transducer that generates IVUS images at frequencies between 30 and 70 MHz, thus increasing the resolution and depth-to-field of the images .
2.3. Interpretation of NIRS data
Upon completion of the automated pullback scan, spectral data are automatically analyzed by a computer-based algorithm that transforms NIR spectra into a probability of LCP presence. The probability is mapped to a color pixel that will generate a digital two-dimensional color map of the artery called the NIRS chemogram, which represents the probability of the presence of LCP over the scanned segment of a vessel ( Figure 3 ). On the longitudinal chemogram, the
Chemometrics is the methodology applied by NIRS technology to analyze lipid content in atherosclerotic arteries . The NIRS system was used in an extensive
The lipid-core burden index (LCBI) is a measure of the lipid burden within the scanned region, calculated by dividing the number of yellow pixels that exceed an LCP probability of 0.6 per million by the total number of valid pixels in the segment, then multiplied by a factor of 1000 (LCBI range: 0–1000). Other measures can be computed on the chemogram image, such as the LCBI of a region of interest (ROI) and the maximum LCBI of the 4-mm region within the highest lipid burden within the ROI (maxLCBI4mm) [26, 27, 35, 36, 39]. It has been shown that a high LCBI detected in coronary plaques is associated with an increased risk of future cardiovascular events and periprocedural complications (see Section 2.6), which suggests that LCBI could be a useful biomarker for risk assessment and therapeutic efficacy in future clinical trials.
2.4. Validation of the NIRS-imaging system
2.4.1. Preclinical and autopsy studies
Autopsy, animal, and human studies have been carried out to test the utility and safety of NIRS for the purpose of eventually bringing this technology to patients in the catheterization laboratory. Cassis and Lodder first demonstrated the ability of NIRS to accurately identify low-density lipoprotein (LDL)
The first study to test the hypothesis that NIR spectroscopy could identify plaque composition and features associated with plaque vulnerability, defined by histology as the presence of lipid pool, thin fibrous cap (<65 μm by ocular micrometry), and inflammatory cell infiltration, was performed in 199 human aortic samples obtained at the time of autopsy . An algorithm was constructed using NIR spectra obtained from 50% of the samples (calibration set) and was then tested on unknown samples (validation set) to determine its ability to identify high-risk features as determined by histology. Spectra associated with each of the three histological features of interest were defined by the results obtained from the calibration set. The main findings of this study were that NIRS could identify histology features associated with plaque vulnerability in human plaques
Since the intention of inventers of the NIRS system was to commercialize a catheter-based instrument that could assess plaques in coronary arteries
2.4.2. Autopsy calibration and validation studies
The catheter-based system was improved with the addition of an automated pullback and rotation device allowing the system to circumferentially scan the length of a vessel. Calibration and validation studies of NIRS for the detection of LCP were first performed in human autopsy specimens of coronary arteries [16, 35]. The largest
2.4.3. Clinical validation studies
The first use of the NIRS system in coronary arteries of living humans was performed in six patients undergoing elective PCI for stable angina using an early prototype (2001; Lahey Clinic, Burlington, MA) [13, 16, 40]. No device-related adverse events occurred, showing the safety and feasibility of the system to distinguish spectra measured through blood. However, significant motion artifacts were present due to slow-signal acquisition time (2.5 s). In August 2005, an improved ultrafast NIR system prototype was developed with a faster scanning laser and was later used in a feasibility study of 10 patients in 2006 (Lahey Clinic, Burlington, MA). The trial confirmed the safety of the newer improved device and showed its ability to discriminate between signals obtained in the artery and those from blood alone, with no measurable artifacts of motion [16, 40].
A subsequent pivotal study, the SPECTACL (SPECTroscopic Assessment of Coronary Lipid) clinical study, was performed to validate the accuracy of LCP-detected NIRS signals collected in coronary arteries of 106 patients . The study met its primary end point of demonstrating that spectral data could be safely acquired in coronary arteries of patients with the intravascular NIRS system and that the spectra were equivalent to those gathered from autopsy specimens (success rate of 0.83; 95% confidence interval (CI): 0.70–0.93). Thus, this study supported the feasibility of LCP detection in living patients. Subsequent studies showed intra- and inter-catheter reproducibility of automated interpretation of NIR spectra signals [50, 51].
2.5. Comparison with other intravascular imaging modalities for plaque characterization
The most common cause of acute coronary syndromes (ACS) is believed to be coronary artery thrombosis due to the rupture of lipid-rich “
2.5.1. Intravascular ultrasound (IVUS) imaging
Intravascular ultrasound imaging (IVUS) produces cross-sectional images of the lumen and the artery wall
|Spatial resolution (μm)||Depth (mm)||Energy source||Remodeling||Plaque composition||Calcium||Fibrous cap||Lipid core||Thrombus||Macrophages||Neovessels|
|NIRS-IVUS||100–150||10||Near-infrared light + ultrasound||++||−||++||±||++||±||−||−|
2.5.2. Virtual histology (VH) imaging
As compared to conventional invasive ultrasound techniques, radiofrequency (RF) IVUS provides additional information on plaque composition and morphology by spectral analysis of ultrasound backscatter . A color-coded map allows the distinction of different components of atherosclerotic plaques, such as calcification (white), lipid/fibrofatty (light-green), fibrous (green) tissue, and necrotic core (red) . Virtual histology (VH)-IVUS spectral analysis correlates with histopathology studies of plaques and can identify the four plaque components with sensitivity, specificity, and predictive accuracy ranging from 80 to 92% [54, 62, 63]. VH-IVUS detection of LCPs has been associated with higher incidence of clinical events [64, 65] and periprocedural complications during PCI [66–68]. Prospective assessment of vulnerable plaques was performed in the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) trial, a multicenter multimodality study that prospectively analyzed by IVUS and IVUS-VH imaging the coronary arteries of 697 ACS patients . Their findings suggested that the presence of TCFA defined by VH-IVUS (hazard ratio (HR), 3.35; 95% CI, 1.77–6.36;
2.5.3. Optical coherence tomography (OCT)
Optical coherence tomography is an invasive catheter-based imaging modality that measures the intensity and echo time delay of reflected near-infrared light from internal structures in tissues . This technique provides a resolution of 10–20 μm
2.5.4. Near-infrared spectroscopy (NIRS)
In contrast to IVUS, RF-IVUS, and OCT, which collect structural information, NIRS is unique for its ability to directly identify the chemical composition of the arterial wall and assess the presence of the LCP. NIRS detects unequivocal fingerprints from lipid core that is not affected by signal loss behind calcium due to acoustic shadowing, as it can occasionally preclude grayscale IVUS analysis, and the validation of NIRS included both calcified and non-calcified lipid cores in the definition of LCP . NIRS alone does not provide information about structural anatomic parameters, such as vessel remodeling, plaque thickness, lumen area, and calcification . However, as previously mentioned, the combined NIRS-IVUS-imaging catheter allows co-registration of both IVUS and NIRS data, which gives information on both plaque composition and morphology. NIRS-IVUS has shown to improve LCP detection, by comparison to IVUS, in calcified plaques as well as in lesions with small plaque burden . The combined measures of plaque burden and LCBI improved the accuracy of fibroatheroma detection as compared with plaque burden alone by grayscale IVUS. Indeed, Puri et al.  conducted an
Several studies have compared NIRS with other intravascular-imaging modalities for LCP detection. It was previously shown that large plaque area measured by grayscale IVUS was more often associated with lipid accumulation/LCP detected by NIRS [19, 80]. However, Brugaletta et al.  found a weak correlation between the VH necrotic core content of the plaque and the block chemogram probability values (
In summary, there are important differences in LCP detection between different intravascular-imaging modalities, owing to their different imaging properties and limitations. As previously mentioned, OCT has the highest resolution but the weakest tissue penetration, limiting assessment of plaque burden and overall plaque volume . While IVUS-VH and OCT require image interpretation for the detection of LCP, NIRS provides automated LCP detection without the need for manual imaging processing, facilitating its use in the catheterization laboratory and enabling rapid ad hoc clinical decision making during procedures. Moreover, OCT and NIRS can image through calcified lesions, whereas IVUS cannot. VH-IVUS can incorrectly misclassify intracoronary stents as calcium surrounded by necrotic core, a major limitation that is not found with OCT and NIRS imaging . From the strengths and weaknesses of each individual imaging modality, it appears that the combination of two or more imaging technologies could improve LCP and vulnerable plaque detection .
2.6. NIRS-IVUS clinical applications
There is growing evidence from multiple studies of the clinical applications and value of the NIRS-IVUS imaging modality, including identifying the culprit lesion in ACS, optimizing PCI procedure, identifying plaques at high risk of periprocedural complications, for risk stratification, monitoring lipid-lowering therapy, and assessing plaque vulnerability (e.g., Table 3 ) .
|Setting||Study or authors||Publishing year||Clinical end point(s)||Results, references|
|LCP detection and ||SPECTACL||2009||106||(1) Evaluate the similarities of NIRS spectra obtained in patients to spectra previously obtained and validated by histology in autopsy specimens;(2) to assess the safety of the device; and (3) to quantify the presence of LCP at target and non-target sites||NIRS system enables to safely obtain spectral data in patients that were similar to those from autopsy specimens and results demonstrated the feasibility of invasive detection of coronary LCP |
|Plaque characterization||Brugaletta et al.||2011||31||Compare the findings of NIRS, IVUS-VH and IVUS grayscale obtained in matched coronary vessel segments of patients undergoing coronary angiography||Larger plaque area by grayscale IVUS was more often associated with either elevated percentage of VH derived-necrotic core (NC) or LCP by NIRS; correlation between LCP detected by NIRS and NC by VH was weak |
|Pu et al.||2012||66||Evaluate NIRS combined with IVUS to provide novel information on human coronary plaque characterization||Combining NIRS and IVUS contributes to plaque characterization |
|Vulnerable plaque||ATHEROREMO-NIRS||2014||203||Determine the long-term prognostic value of intracoronary NIRS as assessed in a nonculprit vessel in patients with CAD||CAD patients with an LCBI ≥ 43.0 had a fourfold risk of MACE during 1-year follow-up |
|Madder et al.||2016||121||Evaluate the association between large lipid-rich plaques (LRP) detected by NIRS at non-stented sites in a target artery and subsequent MACCE||Detection of large LRP by NIRS (maxLCBI4mm ≥400) at non-stented sites in a target vessel was associated with an increased risk of future MACCE |
|Acute coronary syndrome||Madder et al.||2012||60||Determine the frequency of LCP at target and remote sites in ACS vs. stable angina patients||Target lesions responsible for ACS were frequently composed of LCP; LCP in culprit and non culprit lesions were more common in patients with ACS vs. stable angina patients |
|Madder et al.||2013||20||To describe NIRS findings in culprits lesions of STEMI patients||maxLCBI4mm > 400 detected in vivo by NIRS is a threshold for identification of STEMI culprit plaques |
|Madder et al.||2015||81||Assess the lipid burden of culprit lesions in NSTEMI and UA patients||LCP similar to those detected at STEMI culprit sites were detected at culprit sites of NSTEMI and UA patients |
|Periprocedural MI||COLOR registry||2011||62||Analyse the relationship between the presence of large LCP detected by NIRS and periprocedural MI||NIRS provides a rapid and automated detection of extensive LCPs that are associated with a high risk of periprocedural MI |
|Raghunathan et al.||2011||30||Evaluate if an association between the presence and extend of LCP detected by NIRS before PCI and periprocedural MI||PCI of LCP detected lesions by NIRS is associated with increased risk of MI after PCI |
|Maini et al.||2013||77||Evaluation of LCP modification with coronary revascularization and its correlation with periprocedural MI||Plaque modification can be performed by interventional methods and evaluated with NIRS; axial plaque shifting is an acute prognostic marker for postprocedural MI |
|PCI optimization||Dixon et al.||2012||69||Compare the target lesions length using NIRS combined with angiography vs. angiography alone||Patients undergoing stent implantation could have LCP extended beyond angiographic margins of the initial target lesion using QCA alone |
|Hanson et al.||2015||58||Assess the prevalence of plaque burden and LCP extended beyond angiographic borders of target lesions||NIRS-IVUS imaging demonstrates that target lesion length is commonly underestimated by angiography alone |
|Ali et al.||2013||65||Characterize neointimal composition of in-stent restenosis in both BMS and DES using a multimodality approach with OCT and NIRS-IVUS||In-stent thin-cap neoatherosclerosis is more prevalent, more diffusely distributed across stented segment and is associated with increased periprocedural MI in DES compared with BMS |
|Madder et al.||2016||120||Evaluate NIRS-IVUS system findings of increased lipid signals in pre-existing stents, speculated to indicate neoatherosclerosis, and compare with a control group of freshly implanted stents, in which any lipid signal originates from fibroatheroma under the stent||Detection of LCP in pre-existing stents by NIRS alone is not reliable evidence of neoatherosclerosis, as the lipid signal may originate from fibroatheroma under the stent |
|Monitoring lipid-lowering therapies||YELLOW||2013||87||Determine the impact of short-term intensive statin therapy (Rosuvastatin 40 mg OD) on intracoronary plaque content||Short-term intensive treatment with statin was associated with a significant reduction in LCBI / lipid content compared to standard therapy |
|Prevention of PCI complications||Brilakis et al.||2012||9||Investigate whether the use of a distal embolic protection device might prevent complications of LCP interventions||The use of a distal protection device frequently resulted in embolized material retrieval after stenting of native coronary artery lesions with large LCP |
|CANARY||2015||85||Evaluate if a distal protection device reduce postprocedural MI for PCI of LCP lesions||Distal protection device dis not reduce postprocedural MI |
|Erlinge et al.||2015||18||Evaluate if aspiration thrombectomy reduces the lipid content of culprit plaques by NIRS-IVUS in ACS patients assessed||Thrombus aspiration resulted in a 28% reduction in lipid content by performing aspiration thrombectomy in culprit lesion |
In vivodetection of culprit lesions in ACS
Several studies have evaluated NIRS detection of LCP, shown by an increased LCBI, at the site of culprit lesions associated with coronary events. Madder et al.  performed NIRS imaging in culprit vessels of 20 patients with acute ST-segment elevation myocardial infarction (STEMI) and compared their findings with spectra analysis in nonculprit segments of the artery and with autopsy control segments. The maxLCBI4mm was 5.8-fold higher in STEMI culprit segments than in 87 nonculprit segments of the STEMI culprit vessel (median (interquartile range (IQR)): 523 [445 to 821] vs. 90 [6 to 265];
Similar NIRS findings of lipid burden were observed in culprit lesions of patients in non-ST segment elevation myocardial infarction (NSTEMI) [18, 77]. LCPs are more common in patients with ACS compared to stable angina patients. From the 81 NSTEMI and unstable angina (UA) patients who underwent culprit vessel NIRS imaging prior to stenting, non-STEMI culprit segments had a 3.4-fold greater maxLCBI4mm than nonculprit segments (448 ± 229 vs. 132 ± 154,
2.6.2. Association with cardiovascular risk factors
A recent clinical study has evaluated the association between clinical risk factors and blood characteristics of vascular inflammation and lipid content/LCP visualized by NIRS. de Boer et al.  reported the use of NIRS in a nonculprit coronary artery in 208 patients undergoing percutaneous coronary intervention or invasive diagnostic coronary exploration for various indications. It was found that male gender, hypercholesterolemia, and the presence of multivessel CAD were modestly associated with higher LCBI values on NIRS. A history of peripheral vascular disease and/or cerebral disease and the use of beta-blockers were positively associated with LCBI, while biomarkers such as blood lipids and high-sensitivity C-reactive protein were not. All clinical characteristics reflecting patients with high CAD risk explained only 23% of the variability in LCBI. Moreover, the LCBI on NIRS and the percentage area of plaque burden determined by IVUS were modestly correlated (
2.6.3. Assessing plaque vulnerability and risk stratification
Retrospective autopsy studies have revealed specific histological culprit lesion morphologies in patients suffering from an ACS, which has created an enthusiasm in the use of intravascular coronary artery imaging in search of the “
The first prospective human study, published in 2014, has evaluated the association of high LCP by NIRS and cardiovascular events. The ATHEROREMO-NIRS (The European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis—Near-Infrared Spectroscopy) trial is a prospective, observational study that aimed to evaluate the prognostic value of NIRS in a nonculprit coronary artery from 203 patients referred for angiography due to stable angina or ACS . The results showed that the 1-year cumulative incidence of all-cause mortality, non-fatal ACS, stroke, and unplanned coronary revascularization was 4-fold increased in patients with an LCBI equal or above to the median value of 43.0 compared to those with an LCBI value below the median (adjusted HR: 4.04; 95% CI: 1.33–12.29;
The detection of fibroatheroma could help to identify culprit lesions in ACS patients, predict lesions subject to periprocedural complications, could allow optimal stent selection, and reduce the rate of stent restenosis. Whether the detection of fibroatheroma using NIRS-IVUS will prevent future events is currently being studied in several trials, including the Lipid-Rich Plaque study (LCP; Clinical Trials.org Identifier: NCT02033694), PROSPECT II ABSORB trial (A Multicentre Prospective Natural History Study Using Multimodality Imaging in Patients With acute Coronary Syndromes; Clinical Trials.org Identifier: NCT02171065), and ORACLE-NIRS trial (Lipid cORe Plaque Association With CLinical Events: a Near-InfraRed Spectroscopy Study; Clinical Trials.org Identifier: NCT02265146).
2.6.4. Optimizing percutaneous coronary intervention procedures
Visual estimation of a coronary stenosis on a two-dimensional (2D) angiography or quantitative coronary angiography (QCA) of lesion lengths is often misleading from image foreshortening and underestimation of plaque burden. IVUS offers accurate length measurement during automated pullback, proximal and distal reference diameter of a vessel, and enables to evaluate the presence and extent of calcifications . The ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) study, a prospective, multicenter, nonrandomized “all-comers” registry of 8583 consecutive patients, showed that IVUS-guidance PCI, performed in 39% of patients, was associated with reduced 1-year rates of MACE (3.1% vs. 4.7%; adjusted HR, 0.70; 95% CI: 0.55–0.88;
The use of combined NIRS-IVUS imaging may further optimize stent implantation by accurate identification of lipid margins, and thus cover all the segments with high lipid burden. Dixon et al.  analyzed 75 lesions with NIRS imaging and demonstrated that lipid-core plaque extended beyond the angiographic margins of the initial target lesion in 16% of cases. Hanson et al.  showed that atheroma, defined as plaque burden >40% or LCP, extended beyond angiographic margins in 52 of the 58 lesions analyzed with NIRS-IVUS (90% of lesions), with a mean lesion length that was significantly longer when assessed by NIRS-IVUS as compared with angiography alone (19.8 ± 7.0 vs. 13.4 ± 5.9 mm;
Detection of lipid core in a lesion has also been used as one of the factors to consider in the decision to implant a bare metal stent (BMS) or a drug-eluting stent (DES). Several studies have demonstrated a greater frequency of stent thrombosis after DES implantation when struts were penetrating into a lipid-rich necrotic core plaque rather than in a non-yellow (fibrous) plaque [103, 104]. The absence of struts coverage by the formation of a neointima layer during vessel’s healing process was seen with both DES and BMS implantation in lipid-rich plaques, which is likely the underlying mechanism of stent thrombosis seen in those patients [105, 106]. Neoatherosclerosis is an important contributor to late-stent thrombosis with newer generation DES, as well as late in-stent restenosis. Histologically, neoatherosclerosis is characterized by the accumulation of lipid-laden macrophages within the neointima with or without necrotic core formation and/or calcification and can occur months to years following stent placement . Originally described in postmortem studies, neoatherosclerosis has more recently been detected by intracoronary imaging. Ali et al.  used NIRS and OCT to assess the development of neoatherosclerosis in 65 consecutive patients with symptomatic in-stent restenosis. The prevalence of LCP within neointimal hyperplasia segments was 89% using NIRS versus 62% using OCT. Neoatherosclerosis was associated with significantly reduced minimal cap thickness with plaque rupture occurring exclusively in those patients. Moreover, DES had a higher prevalence and earlier occurrence of neoatherosclerosis, thinner cap, and more lipid burden and density. However, LCP identified by NIRS alone was not associated with periprocedural MI during treatment for in-stent restenosis, which reflects the limited ability of NIRS to differentiate lipid located within the neointimal tissue from a lipid core located underneath stent struts. Nevertheless, postmortem imaging and subsequent histology analysis showed that NIRS could correctly characterize lipid despite the presence of metal struts. Similar findings were reported in a study published by Madder et al. , whereas NIRS was not reliable for neoatherosclerosis detection when used as the sole imaging modality for LCP detection. The NIRS lipid signal could not distinguish neoatherosclerosis from fibroatheroma underlying the stent. No doubt that NIRS can detect coronary LCP, but it seems unlikely suitable as a standalone technique for accurate neoatherosclerosis detection and that the adjunction of IVUS or OCT will be required to determine the position of NIRS lipid signal relative to the underlying stent struts .
It was proposed that the growth of neointima tissue on the top of a vulnerable plaque might increase the thickness of the fibrous cap [103, 110, 111]. Brugaletta et al.  reported the ability of bioresorbable vascular scaffold (BVS) implantation to promote the growth of neointimal tissue, which acts as a barrier to isolate vulnerable plaques. An ongoing trial, the PROSPECT II ABSORB sub-study trial (Clinical Trials.org Identifier: NCT021711065), will randomize patients with plaques at high risk of causing future coronary events (plaque burden ≥70%) to receive an AbsorbTM BVS (Abbott Vascular, IL, USA) with optimal medical therapy (OMT) versus OMT alone. This sub-study aims to evaluate the changes in the plaque at 2 years follow-up. Clinically, large LCPs have been shown to be associated with MACE, especially periprocedural myocardial infarction . Whether lipid burden influences long-term outcomes following stent implantation remains elusive.
2.6.5. Prevention of periprocedural complications
Approximately 3–15% of percutaneous coronary interventions are complicated by periprocedural myocardial infarction (PPMI) and no-reflow, in part by distal embolization of intraluminal thrombus and/or lipid-core plaque content, which is associated with adverse long-term outcomes [113, 114]. It was reported that periprocedural MIs are associated with increased atherosclerotic burden and large LCPs [115–118]. Indeed, embolization of the lipid core after stent implantation in a plaque with high lipid content has been identified as an important cause of periprocedural no-reflow and MI with and without the presence of intracoronary thrombus [118–120]. A pilot study performed in nine patients using an embolic protection device showed that embolized material consisted in fibrin and platelet aggregates, which reflects the highly thrombogenic content of necrotic core of large atheroma plaques and LCP [98, 120, 121]. In a sub-study of the COLOR (Chemometric Observation of Lipid-Core Plaques of Interest in Native Coronary Arteries) registry, a prospective multicenter observational study aiming to determine a relationship between NIRS-defined high LCBI and periprocedural MI, Goldstein et al.  analyzed the cardiac biomarkers of 62 stable patients undergoing PCI. The main findings were that periprocedural MI, defined in the study as a postprocedural elevation above three times the upper limit of normal (ULN) for either creatine kinase-MB (CK-MB) or cTnI measured 4–24 h after PCI, occurred in nine patients (14.5%) and was more common among patients with a maxLCBI4mm ≥ 500 (7 of 14 patients, 50%) versus patients with a maxLCBI4mm < 500 (2 of 48 patients, 4.2%). The authors concluded that a high LCP, defined as a maxLCBI4mm ≥ 500, was associated with periprocedural events. These results are concordant with the registry study conducted by Raghunathan et al. , in which the analysis of 30 patients who underwent pre-procedure NIRS imaging showed a postprocedural increase of CK-MB more than three times the UNL in 27% of patients with a ≥1 yellow blocks (
Distal embolization, as an important mechanism of periprocedural MI, was further supported by several studies that have demonstrated a significant decrease in the size of LCP after stenting [122–124]. Stone et al. showed in the CANARY trial that LCP measured as LCBI by NIRS in the stented vessels reduces with PCI treatment, with a significant reduction of median LCBI from 143.2 before PCI to 17.9 after PCI (
In order to prevent periprocedural MI during PCI, several strategies were proposed during stenting procedures, including aspiration thrombectomy, embolization distal-protection devices, vasodilators, intensive anticoagulation, and antiplatelet therapies. The CANARY (Coronary Assessment by NIR of Atherosclerotic Rupture-Prone Yellow) trial randomized 85 stable angina patients undergoing stent implantation of a single native coronary lesion and pre-procedure NIRS-defined maxLCBI4mm ≥ 600 to PCI with or without distal-protection filter . Among the 31 randomized cases with a maxLCBI4mm≥ 600, there was no difference in the rates of periprocedural MI with or without the use of distal-protection filter (35.7 vs. 23.5%, respectively; relative risk 1.52; 95% CI: 0.50–4.60,
Thrombectomy is often used to aspirate thrombus and restore blood flow in the culprit vessel during primary PCI in STEMI patients. The clinical benefits of routine thrombus aspiration remain a matter of debate, since the TAPAS (Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction) study demonstrated a reduction of mortality while larger studies such as TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) and TOTAL (Trial of Routine Aspiration Thrombectomy with PCI versus PCI Alone in Patients with STEMI) did not show a reduction of cardiovascular mortality, with an increased rate of stroke at a 30-day follow-up in the TOTAL trial [126–128]. Erlinge et al.  performed NIRS-IVUS imaging in 18 ACS patients to examine if aspiration thrombectomy reduced the lipid content of ACS culprit plaques. The culprit lipid content was quantified by NIRS-IVUS before and after thrombectomy as the lipid-core burden index (LCBI), and aspirates were examined by histological staining for lipids, calcium, and macrophages. Culprit lesions were found to have high lipid content prior to thrombectomy, which resulted in a 28% reduction in culprit lesion lipid content (pre-aspiration LCBI 466 ± 141 vs. post-aspiration 335 ± 117,
As aforementioned, the use of intracoronary NIRS-IVUS imaging for accurate identification of LCP lesions prone to embolize, as well as different treatment strategies, for periprocedural MI prevention are attractive approaches, however their clinical benefits on myocardial salvage and prevention of embolization remains to be demonstrated in future studies.
2.6.6. Monitoring effects of lipid-lowering therapies
It is well known that statin therapy reduces rates of cardiovascular events in secondary prevention. The pharmacological effects of specific lipid-reducing agents that reduce free and esterified cholesterol could be evaluated with NIRS, as it informs on the lipid content of coronary artery plaques over time. The demonstration of markedly reduced LCBI values in a patient after 1 year of high-dose rosuvastatin therapy was the first indication that NIRS-IVUS could be used to evaluate the effect of systemic anti-atherosclerotic medical therapy . In the YELLOW (Reduction in Yellow Plaque by Aggressive Lipid-Lowering Therapy) trial, Kini et al.  prospectively randomized 87 patients with multivessel coronary artery disease undergoing PCI with one culprit and one nonculprit hemodynamically significant lesions, defined by fractional flow reserve (FFR <0.80), to receive intensive statin therapy (rosuvastatin of 40 mg daily) or standard lipid-lowering therapy. The nonculprit lesions had a baseline assessment by NIRS-IVUS and FFR, prior to randomization. Rosuvastatin therapy resulted in a significant reduction in the plaque lipid content/maxLCBI4mm compared to standard therapy. The significant reduction in maxLCBI4mm associated with intensive statin therapy was observed across subgroups of the study population, based on age, gender, presence of diabetes, and baseline lipid profile. However, no significant changes were observed for the maxLCBI4mm and LCBI measurements at the lesion site in the standard lipid treatment group at follow-up. Although baseline LCBI was significantly higher in patients randomly allocated to intensive versus standard therapy, the YELLOW trial highlights that LCP measured by NIRS was associated with CAD and that it could be a potential tool to monitor regression of the disease in phase II clinical trials evaluating novel anti-atheromatous therapies.
A similar study of the effect of rosuvastatin treatment on the coronary plaque composition and necrotic core, the IBIS-3 (Integrated Biomarker and Imaging Study 3) trial, failed to demonstrate a significant reduction of necrotic core volume or LCBI under intensive rosuvastatin therapy for 1 year . The effects of high-dose statin therapy are being further investigated in the YELLLOW II trial (Clinical Trials.org Identifier: NCT01837823), a phase II clinical study, that aims to assess the regression of plaque lipid content and changes in plaque morphology from atherosclerotic lesions after 8–12 weeks of high-dose statin therapy by utilizing NIRS, IVUS, and OCT imaging modalities in the coronary arteries.
2.7. Limitations of the technology
Near-infrared spectroscopy (NIRS) identifies the chemical signature of the lipid component, specifically lipid core-containing coronary plaque (LCP). The main limitations of NIRS technology are the lack of information regarding the lumen, plaque anatomy, and status of the fibrous cap or its attenuation. Although NIRS may be one of the most sensitive modalities to detect lipid-core plaques, it cannot provide information on the depth of the lipid core. Moreover, the accurate measurement of lipid volume/burden with NIRS has not been validated . To overcome these pitfalls, a new combined imaging catheter adding intravascular ultrasound (IVUS) imaging was developed. However, since intravascular ultrasound has a low sensitivity to visualize lipid inside a plaque, the additional value of this new system will require further evaluation .
The clinical relevance of imaging specific features of the vulnerable plaque for risk stratification and clinical decision making remains unclear. Higher-resolution imaging modalities, such as OCT, better assessed determinants of vulnerable plaques than NIRS; however, there is currently no commercialized system combining OCT and NIRS modalities. The prognostic utility and incremental value of NIRS when associated with biomarkers of plaque vulnerability assessed by IVUS (plaque burden, MLA, and remodeling) remains to be investigated [26, 133]. Many studies have brought evidence that IVUS-guided PCI achieves superior outcomes compared to angiography guidance alone . The potential value of adding NIRS for lipid-rich plaques at risk of embolization and for a complete coverage of LCPs remains to be investigated. NIRS-IVUS-imaging modality is an invasive diagnostic modality that targets patients in the setting of secondary prevention, thus precluding its utilization for primary prevention, along with other invasive imaging technologies.
2.8. Future trials and perspective
NIRS-IVUS-imaging technology is improving and should become a sensitive modality for coronary plaque characterization. A new algorithm for collagen detection has been developed using the same spectroscopy signal, which enables to detect the amount of fibrous tissue over the LCP (thin or thick fibrous cap) . This technology will be further optimized by adding a recently developed, but not yet available, high-resolution IVUS, which will allow to accurately differentiate between thin and thick fibrous caps. Co-registration of NIRS with other imaging modalities is also being developed. The use of combined OCT-NIRS catheters has been recently demonstrated as a proof of concept .
NIRS-IVUS has also been used in the carotid arteries to detect LCP, which could represent a suitable imaging modality to determine the risk of stroke or the risk of complications during carotid stent placement or endarterectomy. However, this new clinical application remains to be validated in future studies .
Multiple prospective outcome studies are currently ongoing to evaluate the ability of NIRS-IVUS imaging to detect vulnerable plaques that are likely to cause future adverse events. Among those studies are the LRP trial (Lipid-rich Plaque Study; Clinical Trial.org Identifier: NCT02033694), the PROSPECT II ABSORB trial (Providing Regional Observations to Study Predictors of Events in the Coronary Tree II; Clinical Trial.org Identifier: NCT02171065), and the ORACLE-NIRS trial (Lipid-core plaque association with clinical events: a near-infrared spectroscopy study; Clinical Trial.org Identifier: NCT02265146). The YELLOW II trial (NCT01837823), which aims to evaluate the effects of rosuvastatin treatment on lipid content after 8–10 weeks of treatment regimen, has completed patient enrolment but results are still pending. Another trial has been completed and awaiting for results publication, the NIRS-TICAGRELOR trial (Clinical Trial.org Identifier: NCT02282332), which aims to evaluate the effect of the P2Y12 inhibitor ticagrelor (AstraZeneca, Cambridge, England) on plaque stabilization and reduction of inflammation by NIRS-defined reduction of LCBI in patients on long-term statin therapy undergoing non-urgent PCI.
NIRS is a promising tool for the detection of vulnerable plaques in CAD patients, PCI-guidance procedures, and assessment of lipid-lowering therapies. NIRS-IVUS has been shown to be a reliable and reproducible modality for the detection of intracoronary LCPs, with validation using the current gold-standard, histology. It has already been shown that this imaging modality is highly specific for identifying NSTEMI and STEMI culprit plaques, that it can be used to follow the progression of vulnerable plaques over time, and to evaluate the effect of lipid-lowering therapies and intracoronary devices. Moreover, preliminary data have shown that NIRS-IVUS-imaging technology can identify vulnerable patients. Multiple ongoing clinical trials will hopefully validate this tool for vulnerable plaque and patient detection, as well as for treatment management and follow-up of patients with CAD.
Acute coronary syndrome
Bioresorbable vascular scaffold
Coronary artery disease
Coronary artery bypass graft
Conventional coronary angiography
Cardiac troponin I
US Food and Drug Administration
Frequency-domain optical coherence tomography
Fractional flow reserve
Lipid-core burden index
Major adverse cardiac events
Major adverse cardiac and cerebrovascular events
Maximum lipid-core burden index in 4-mm region
Minimal lumen area
Non-ST segment elevation myocardial infarction
Optical coherence tomography
Optical frequency domain imaging
Optimal medical therapy
Percutaneous coronary intervention
Periprocedural myocardial infarction
Quantitative coronary angiography
Region of interest
Sudden cardiac death
ST-segment elevation myocardial infarction
Upper limit of normal