Intracoronary Plaque Assessment Using Near-Infrared Spectroscopy Technology: A Valuable Tool?

Coronary angiography allows for rapid, accurate luminal assessment. However, where angiography falls short is in evaluation of the vessel wall, which is where plaque development is taking place (Figure 1).^1,2 Studies have also shown that vessel remodeling can obscure underlying plaque on angiography; therefore, technology that can help accurately visualize underlying plaque burden within the vessel wall that is not flow limiting can allow for appropriate risk stratification of patients and help tailor treatment strategies accordingly. It is important to identify this underlying “hidden” plaque, because it is prone to rupture and forms the bedrock of acute coronary syndromes and sudden cardiac death.³

 

Invasive technologies such as intravascular ultrasound (IVUS), radiofrequency IVUS, and optical coherence tomography (OCT) have all helped look at the vessel wall with reasonable results. While differences in these technologies are beyond the scope of this discussion, it is important to mention that limiting factors such as differences in resolution and attenuation due to calcification, amongst other factors, have led to a low specificity for detection of thin-cap fibroatheromas (TCFAs, also known as “vulnerable plaques”) that have the potential to rupture. 

 

One of the technologies currently available in the percutaneous coronary intervention (PCI) armamentarium is known as near-infrared spectroscopy (NIRS). NIRS can help determine the distribution and chemical composition of underlying plaque, and allows for the identification of vulnerable plaques. When combined with another imaging modality such as IVUS, it provides the ability to identify plaque distribution and composition, and assess the length of the lesion, along with the degree of luminal stenosis and degree of vessel remodeling, without being affected by many of the limitations of other intracoronary imaging modalities (Table 1). The TVC Imaging system (Infraredx), which combines NIRS with IVUS, allows for the acquisition of this information during assessment of the coronary tree. 

 

Coronary artery disease still contributes heavily towards morbidity and mortality worldwide, and while improvements in medications, stent design, and stent delivery systems have allowed for improvements in the treatment of acute coronary syndromes, an area where technology has lagged is in being able to detect patients at risk of developing acute coronary syndrome/sudden cardiac death. NIRS paired with IVUS appears to be a tool that can help identify patients at risk of future coronary events by allowing for the improved appreciation of plaque burden and distribution.⁵ 

 

 

NIRS has been used in the physical sciences for years and its application in agriculture for the detection of heavy metal particulate matter in the soil, quality control for agricultural products, optical characteristics of nanoparticles, and even in the telecommunications industry, is well known.⁶ Its medical use dates back to the early 1990’s, when it was first used for the detection of lipid content in animal models, followed by validation in human cadavers.^7,8 It wasn’t until 2008 when Gardner et al published a study on coronary autopsy specimens that proof was finally obtained that NIRS can be used to accurately assess intracoronary plaque burden.⁹ U.S. Food and Drug approval occurred in 2008 and a combination NIRS-IVUS system was approved in 2010. 

 

 

Every compound has a tendency to absorb, reflect, and scatter near-infrared light to different degrees, yielding what can be known as a near-infrared fingerprint. This is the principle used to characterize intracoronary plaque. 

 

The TVC Imaging system functions by giving off near infrared-light in the 800-2500 nm wavelength. These photons then come into contact with surrounding structures and are either reflected, scattered, or absorbed. Based on the amount of light energy that returns to the spectrometer, a signal is generated. Multiple such signals, through image processing, yield qualitative and quantitative information in the form of a chemogram that can help characterize the anatomy of the wall of the coronary artery. 

 

 

The Infraredx IVC Imaging system currently available on the market is a hybrid spectroscopy and IVUS system. It allows for simultaneous evaluation of the structure of the artery via ultrasound and also allows for spectroscopic analysis that provides information regarding the intracoronary lipid burden, i.e., the composition of the vessel wall. 

 

The system is catheter-mounted and delivered over an .014-inch wire into the target vessel. A minimum of a 6 French (Fr) sheath with an appropriate guiding catheter is required for this device, which has a 3.2 Fr crossing profile. The Infraredx catheter consists of a core of optical fibers that rotate 360 degrees at 960 revolutions per minute (rpm) and can image a distance of up to 120 mm at a depth of 1 mm using a bandwidth frequency between 30-70 MHz. Once the catheter is positioned, it is attached to the Nexus controller. The controller provides mechanical rotation and automatic pullback at 0.5 mm/sec. Close to 30,000 measurements are made for every 100 mm of artery scanned. Images are then displayed on the Infraredx console.

 

NIRS Interpretation 

 

The degree of light reflected back to the receiver at the catheter tip helps generate color pixels. These color pixels, depending on the probability of lipid core plaque (LCP) presence, are color coded on to a spectrum. The blocks may be colored red (low probability of a LCP), orange, tan, or yellow (high probability of a LCP).

 

Pixels where information is felt to be indeterminate are coded as black. On the chemogram, the pullback distance is represented on the x-axis, while the rotation angle is represented on the y-axis. The algorithm also generates chemogram blocks that provide color-coded summaries for every 2 mm of distance of a performed pullback. 

 

Since the current NIRS system also contains IVUS, the IVUS images are superimposed onto the chemogram, giving a longitudinal as well as transverse cross-sectional depiction of the artery with concurrent spectroscopic display. 

 

Other than qualitative parameters, quantitative measures are also calculated using the information that is obtained, including the lipid core burden index. This represents the total lipid burden in the segment of the analyzed vessel. The lipid burden is obtained by deriving the ratio of yellow pixels in a given segment to the total number of pixels in that segment, and multiplying it by 1000. The maximum lipid core burden index (LCBI) in a 4 mm segment (LCBI_4mm) describes the region with the highest lipid burden. Studies have shown that in acute coronary syndrome (ACS) patients, a maximum LCBI_4mm >380 is representative of unstable plaque.^10,11

 

 

While spectroscopy was developed primarily to help identify underlying plaque burden, in combination with IVUS, it has found additional clinical use. Use of this system has the potential to help physicians develop further preventive strategies and improve overall outcomes in the sphere of acute coronary syndromes. Some of the practical applications of this technology include: 

1. Detection of culprit lesions. Most of the time, plaque rupture or erosion is responsible for ACS. These plaques tend to have characteristically dense lipid cores. Studies have shown that in different patient populations, plaque density, which is reflected in spectroscopy as max-LCBI, can help identify regions of the coronary artery that are prone to acute occlusion. Madder et al have shown that in ST-elevation myocardial infraction (STEMI) patients, maxLCBI is approximately 6x higher than other segments in the same coronary vessel.¹² Similarly, in non-STEMI patients, maxLCBI tended to be 3.4x higher than matched histological controls, while those with unstable angina had a maxLCBI that was 2.8x higher. In cases where a culprit might not be easily discernible angiographically, spectroscopic analysis might make identification of the culprit segment easier.¹³

 

2. Optimization of percutaneous coronary interventions. Coronary angiography provides a crude assessment of the vessel wall, with PCI tailored only to those affected segments that can be well visualized.4 Trials such as ADAPT-DES demonstrated that the use of IVUS during PCI led to a reduction in major adverse cardiac events compared to simple angiographic stent insertion.¹⁴ A similar concept is applicable to the NIRS-IVUS system, where direct visualization allows for detailed assessment of the region of interest, with NIRS providing additional information regarding the structural composition of the vessel wall. This information allows for the optimization of stent implantation by performing lipid “edge-to-edge” stenting. Prior studies have shown that in 16-62% of cases, LCPs tend to extend beyond stented margins.^4,15 The use of NIRS-IVUS can help operators stent to cover these LCPs in their entirety, and also help reduce stent failure and subsequent major adverse cardiac events.^4,15 

 

3. Prevention of distal embolization. Three percent to 15% of percutaneous procedures suffer from distal embolization causing periprocedural myocardial infarctions (MI), which in turn leads to poor long-term outcomes.^4,16 In the setting of plaque rupture, high lipid content with a dense lipid core can lead to the aforementioned complication, as shown in prior studies.¹⁶ Raghunathan et al showed an increase in CK-MB levels of more than 3 times the upper limit of normal in 11 patients with ≥1 yellow block (high probability of a LCP) on spectroscopy as opposed to none, in 19 patients with no yellow blocks.¹⁷ Similarly, a sub study of the COLOR registry (Chemometric Observation of Lipid-Core Plaques on Interest in Native Coronary Arteries) showed a post-procedural increase in CK-MB or troponin-I levels above the upper limit of normal in those with a max-LCBI >500, indicating distal embolization and periprocedural complications.¹⁸ Strategies to combat this issue include embolic protection devices (EPD), aspiration thrombectomy, the use of vasodilators, and intensive use of antiplatelet/antithrombotic agents; however, the results in terms of improving outcomes have not been consistent, as has been shown in the CANARY trial, where, for example, despite the use of EPDs, the rate of periprocedural MIs was consistent.¹⁹ Therefore, while distal embolization in lipid-rich vulnerable plaques continues to remain a threat, new strategies are needed to combat it effectively and, in turn, improve outcomes. 

 

4. Identifying patients at risk of future coronary events. The ATHEROREMO-NIRS (European Collaborative Project on Inflammation and Vascular Wall Remodeling in Atherosclerosis-Near-Infrared Spectroscopy) prospective analysis looked at patients undergoing PCI for stable angina and showed that patients who had an LCBI greater than the median level had a 4-fold higher risk of stroke, non-fatal ACS, and unplanned coronary revascularization compared to those who were below the median.20 Similar results were also seen in ORACLE-NIRS (lipid cORe plaque association with CLinical events), where 239 patients underwent NIRS and were subsequently followed for approximately 5 years. The study showed that patients with elevated LCBI in a non-PCI target vessel had a higher incidence of major adverse cardiac events.²¹ The Lipid Rich Plaque study is another large, prospective, cohort study that is using NIRS to identify people at risk of future cardiac events, over a period of two years. While the data for prognostication is slowly increasing, the question that remains is whether the identification of lipid-rich plaques with NIRS will help reduce the rates of future coronary events. 

 

5. Tailoring pharmacotherapy based on spectroscopic results. While identification of lipid plaque using NIRs has been established as a useful strategy, whether treating lipid-rich plaques can lead to good outcomes overall is a focus that has met with mixed results. The YELLOW trial (reduction in yellow plaque by aggressive lipid-lowering therapy) was one of the first few studies looking at the concept of using statin therapy to aggressively treat lipid-rich plaques.²² NIRS was used to establish a baseline prior to treatment with statins and the authors found that those undergoing intense treatment with statins did witness a reduction in the lipid content of their fibroatheromas when compared to patients on standard treatment. The IBIS-3 trial, on the other hand, did not show a significant reduction in the necrotic core volume or LCBI after a year of intensive statin therapy.²³ This is still an area being heavily investigated. 

 

 

NIRS appears to be promising technology. Its ability to detect lipid lesions that are not visible on plain angiography is its biggest strength. All data currently available also show that the device is not just easy to use, but has results that are easy to reproduce as well. Moreover, combining NIRS with IVUS has further enhanced its usefulness as an imaging modality. However, all available data are from studies with small sample sizes. Future, larger studies should hopefully offer more answers about the usefulness of this technology in terms of plaque detection, the risk of future coronary events, and the effect of treatment strategies on lipid burden.