Prof Patrick W Serruys MD PhD
Salvatore Brugaletta MD
Hector M Garcia-Garcia MD PhD
Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands and Thorax Institute, Department of Cardiology, Hospital Clinic, Barcelona, Spain
The identification of vulnerable plaques has always been a challenge for interventional cardiologists. Anatomo-pathologists have shown that thin-cap fibroatheromas are most commonly prone to rupture in vivo.(1) The presence of lipid cores (also known as necrotic cores) is one of the most important components of a thin-cap fibroatheroma; however, these lipid core plaques (LCPs) are not detectable using traditional diagnostic methods.(2) Angiography is of limited use because it is used mainly to obtain an image of the lumen of the artery and not of the arterial wall. Previous angiographic studies have also failed to identify those quiescent plaques prone to progression or rupture, as most of them are non-flow limiting.(3–5)
Developing a near-infrared spectroscopy catheter system
A near-infrared spectroscopy (NIRS) catheter has been developed to accurately assess these plaques during cardiac catheterisation. Developing NIRS for use in human coronary arteries has been a complex process, taking over 15 years. Initial studies clearly demonstrated NIRS as a valid methodology for measuring the chemical components of atherosclerotic plaques.(6,7) The next steps involved the development of a catheter-based system, which could access the coronary arteries in vivo and which could rapidly perform the thousands of longitudinal and rotational measurements necessary to image the arteries through flowing blood. The system takes approximately 1000 NIRS measurements for each 12.5mm of artery scanned, and each measurement examines approximately 1–2mm3 of arterial wall perpendicular to the long axis of the catheter and centered on the catheter’s optical tip. This NIRS catheter was well-suited for analysis of LCP in vivo because it could penetrate both the blood and several millimetres into the tissue; it overcame the problem of cardiac motion, because it uses an ultrafast scanning laser, and provides a chemical measure of the lipid-core target of interest. It does not rely on dropout of signal as do intravascular ultrasound (IVUS) and optical coherence tomography (OCT).(8,9)
Autopsy validation study
This catheter was used in an extensive ex vivo study in human coronary autopsy specimens to develop an algorithm for the detection of LCP.(10) A LCP of interest was defined as a fibroatheroma containing a necrotic core at least 0.2mm thick and with a circumferential span of at least 60 degrees on cross-section. This prospective validation of the system for detection of LCP in nearly 2000 individual blocks from 51 hearts yielded an area under the ROC curve of 0.80 (95% CI: 0.76 to 0.85) for average lumen diameters of up to 3.0 mm.(10)
SPECTACL clinical study
Following the autopsy validation study, the SPECTroscopic Assessment of Coronary Lipid (SPECTACL) pivotal clinical study was conducted to determine if the spectra recorded in patients (from whom tissue is not available for validation) were equivalent to the spectra recorded in autopsy specimens (from which tissue was available for histologic validation).(11) This study successfully demonstrated that high-quality NIRS signals, similar to those validated in human coronary autopsy specimens, were obtained from the coronary arteries of living patients, thereby supporting the feasibility of invasive detection of coronary LCPs with this novel system. Excellent reproducibility of the NIRS findings during repeat pullbacks was demonstrated recently.(12)
Further system development
In contrast to IVUS, NIRS does not provide any information about the size of the lumen or of the plaque. In addition, an IVUS backscattering signal has been used for the virtual histological characterisation of coronary plaque through an autoregressive classification system.(13,14) As IVUS–virtual histology (IVUS‑VH) has been studied extensively in the last years, the authors recently compared the findings of IVUS, IVUS-VH and NIRS in a same region of interest, delimited by common side branches. Larger coronary plaques, identified by greyscale IVUS, were more likely to be recognised as LCPs and as necrotic-core rich plaques by NIRS and VH, respectively; however, the correlation between NIRS and VH was poor.(15) The fundamental differences in the principles of each technique, that is VH is based on a pattern classification of the backscattering ultrasound signal, whereas NIRS is based on near-infrared spectral signals, and their respective limitations should be taken into account in the interpretation of the differing results between NIRS and
TVC Imaging: the next generation
To combine compositional and quantitative information on coronary plaques, a next-generation combined NIRS-IVUS catheter (TVC InsightTM catheter) has been developed in a partnership between Infraredex and the Biomedical Engineering Group of the Thoraxcenter in Rotterdam.(16) The TVC Insight catheter was used in ten patients at the Thoraxcenter (SAVOIR trial) and allows simultaneous, co-registered acquisition of structural and compositional information (Figure 2). The device was approved by the FDA in April 2008 and received a CE mark in April 2011.
Early experience with the NIRS device suggested multiple potential uses, all of which will require validation in future studies. Early users of NIRS have, in particular, observed cases in which balloon inflation at the LCP site resulted in no or slow reflow with an associated elevation of myocardial necrosis marker.(16) Pre- and post-scans showing post-intervention disappearance of LCPs lend further evidence to the hypothesis that LCP rupture leads to myocardial infarction by causing distal embolisation of its contents. In several cases, placement of filters distal to such LCPs has resulted in the collection of yellow material following balloon dilatation. These findings could represent the basis of an upcoming randomised clinical trial, testing the ability of an embolic device to prevent a peri-procedural myocardial infarction in cases in which NIRS can predict elevated risk owing to dilatation
Another possible use of the TVC Imaging System in clinical practice would be to assist in decisions regarding the length of artery to be stented. During stenting, sites demonstrating a normal distal and proximal reference diameter are generally chosen for implantation; however, IVUS imaging frequently shows that there could be extensive plaque with expansive remodelling at these sites.(17) In addition, angioscopy studies revealed that placement of a drug-eluting stent over yellow plaque resulted in a higher frequency of thrombosis.(18) With this in mind, NIRS-IVUS would make it possible to avoid placement of the ends of a stent in a LCP. Long-term studies are required to determine whether TVC-guided stent length could result in better clinical outcomes.
The TVC Imaging System also has the potential to guide treatment of lesions causing an intermediate degree of coronary stenosis. As early evidence mounts for the greater propensity for rupture and more rapid progression when LCPs are present, the presence of LCPs in angiographically intermediate stenosis may support a tailored stenting approach. A randomised trial of stenting of such LCP lesions of intermediate stenosis needs to be conducted to test this hypothesis. In particular, Infraredex Inc. has initiated an observational study of cholesterol in coronary arteries to determine the relationship between NIRS findings and subsequent events over a 2-year period (COLOR registry, NCT00831116; see http://clinicaltrials.gov/ct2/show/NCT00831116). The study aims to enroll 1000 patients in 14 centres across the USA.
NIRS-IVUS is also likely to be useful in the choice of lipid modification therapies in some patient subgroups. The presence of extensive LCP might, indeed, indicate the need for more intensive or different types of LDL-lowering therapies. NIRS-IVUS will be also useful in the development of anti-atherosclerosis medications by providing a surrogate endpoint in plaque regression/stabilisation studies. In particular, the ability of NIRS to assess the lipid content of plaques may be a more effective means of identifying the beneficial effect of an agent than IVUS. For testing these hypotheses, the IBIS-3 (Integrated Biomarker and Imaging Study) trial has begun enrolling patients at the Thoraxcenter in Rotterdam in order to determine the effect of intensive rosuvastatin therapy on the content of necrotic core (IVUS-VH) and lipid‑containing regions (NIRS) at 52 weeks in a non-intervened coronary artery.
- Virmani R et al. Pathology of the vulnerable plaque. J Am Coll Cardiol 2006;47(8 Suppl):C13–18.
- Naghavi M et al. From vulnerable plaque to vulnerable patient. Circulation 2003;108(15):1772–78.
- Ambrose JA et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988;12(1):56–62.
- Hackett D et al. Pre-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur Heart J 1988;9(12):1317–23.
- Little WC et al. Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease? Circulation 1988;78 (5 Pt 1):1157–66.
- Wang J et al. Near-infrared spectroscopic characterization of human advanced atherosclerotic plaques. J Am Coll Cardiol 2002;39(8):1305–13.
- Moreno PR et al. Detection of lipid pool, thin fibrous cap, and inflammatory cells in human aortic atherosclerotic plaques by near-infrared spectroscopy circulation 2002;105(8):923–27.
- Madden SP et al. In: Escaned J, Serruys PW (eds) Coronary artery stenosis: imaging, structure and physiology. Toulouse: Europa Edition;2010: 245–61.
- Garcia-Garcia HM et al. Imaging of coronary atherosclerosis: intravascular ultrasound. Eur Heart J 2010;31(20):2456–69.
- Gardner CM et al. Detection of lipid core coronary plaques in autopsy specimens with a novel catheter-based near-infrared spectroscopy system. JACC Cardiovasc Imaging 2008;1(5):638–48.
- Waxman S et al. In vivo validation of a catheter-based near-infrared spectroscopy system for detection of lipid core coronary plaques: initial results of the SPECTACL study. JACC Cardiovasc Imaging 2009;2(7):858–68.
- Garcia BA et al. Reproducibility of near-infrared spectroscopy for the detection of lipid core coronary plaques and observed changes after coronary stent implantation. Catheter Cardiovasc Interv 2010;76(3):359–65.
- Nair A et al. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation 2002;106(17):2200–206.
- Nair A et al. Automated coronary plaque characterisation with intravascular ultrasound backscatter: ex vivo validation. EuroIntervention 2007;3(1):113–20.
- Brugaletta S et al. NIRS and IVUS for characterization of atherosclerosis in patients undergoing coronary angiography. J Am Coll Cardiol Imaging 2011;4(6):647–55.
- Schultz CJ et al. First-in-man clinical use of combined near-infrared spectroscopy and intravascular ultrasound: a potential key to predict distal embolization and no-reflow? J Am Coll Cardiol 2010;56(4):314.
- Nissen SE. Application of intravascular ultrasound to characterize coronary artery disease and assess the progression or regression of atherosclerosis. Am J Cardiol 2002;89(4A):24B–31B.
- Oyabu J et al. Angioscopic evaluation of neointima coverage: sirolimus drug-eluting stent versus bare metal stent. Am Heart J 2006;152(6):1168–74.