Stephen T. Sum

Detection of Lipid Core Coronary Plaques in Autopsy Specimens With a Novel Catheter-Based Near-Infrared Spectroscopy System

OBJECTIVES This study sought to assess agreement between an intravascular near-infrared spectroscopy (NIRS) system and histology in coronary autopsy specimens. BACKGROUND Lipid core plaques cannot be detected by conventional tests, yet are suspected to be the cause of most acute coronary syndromes. Near-infrared spectroscopy is widely used to determine the chemical content of substances. A NIRS system has been developed and used successfully in 99 patients. METHODS Scanning NIRS was performed through blood in 212 coronary segments from 84 autopsy hearts. One histologic section was analyzed for every 2 mm of artery. Lipid core plaque of interest (LCP) was defined as a lipid core >60 degrees in circumferential extent, >200-microm thick, with a mean fibrous cap thickness <450 microm. The first 33 hearts were used to develop the algorithm; the subsequent 51 validation hearts were used in a prospective, double-blind manner to evaluate the accuracy of NIRS in detecting LCP. A NIRS-derived lipid core burden index for an entire artery was also validated by comparison to histologic findings. RESULTS The LCPs were present in 115 of 2,649 (4.3%) sections from the 51 validation hearts. The algorithm prospectively identified LCP with a receiver-operator characteristic area of 0.80 (95% confidence interval [CI]: 0.76 to 0.85). The lipid core burden index detected the presence or absence of any fibroatheroma with an area under the curve of 0.86 (95% CI: 0.81 to 0.91). A retrospective analysis of lipid core burden index conducted in extreme artery segments with either no or extensive fibroatheroma yielded an area under the curve of 0.96 (95% CI: 0.92 to 1.00), confirming the accuracy of spectroscopy in identifying plaques with markedly different lipid content under ideal circumstances. CONCLUSIONS This novel catheter-based NIRS system accurately identified lipid core plaques through blood in a prospective study in coronary autopsy specimens. It is expected that this novel capability will be of assistance in the management of patients with coronary artery disease.

In vivo validation of a catheter-based near-infrared spectroscopy system for detection of lipid core coronary plaques: initial results of the SPECTACL study.

OBJECTIVES To determine whether catheter-based near-infrared spectroscopy (NIRS) signals obtained with a novel catheter-based system from coronaries of patients are similar to those from autopsy specimens and to assess initial safety of NIRS device. BACKGROUND An intravascular NIRS system for detection of lipid core-containing plaques (LCP) has been validated in human coronary autopsy specimens. The SPECTACL (SPECTroscopic Assessment of Coronary Lipid) trial was a parallel first-in-human multicenter study designed to demonstrate the applicability of the LCP detection algorithm in living patients. METHODS Intracoronary NIRS was performed in patients undergoing percutaneous coronary intervention. Acquired spectra were blindly compared with autopsy NIRS signals with multivariate statistics. To meet the end point of spectral similarity, at least two-thirds of the scans were required to have >80% of spectra similar to the autopsy spectra. RESULTS A total of 106 patients were enrolled; there were no serious adverse events attributed to NIRS. Spectroscopic data could not be obtained in 17 (16%) patients due to technical limitations, leaving 89 patients for analysis. Spectra from 30 patients were unblinded to test the calibration of the LCP detection algorithm. Of the remaining 59 blinded cases, after excluding 11 due to inadequate data, spectral similarity was demonstrated in 40 of 48 spectrally adequate scans (83% success rate, 95% confidence interval: 70% to 93%, median spectral similarity/pullback: 96%, interquartile range 10%). The LCP was detected in 58% of 60 spectrally similar scans from both cohorts. CONCLUSIONS This intravascular NIRS system safely obtained spectral data in patients that were similar to those from autopsy specimens. These results demonstrate the feasibility of invasive detection of coronary LCP with this novel system. (SPECTACL: SPECTroscopic Assessment of Coronary Lipid; NCT00330928).

Detection by Near-Infrared Spectroscopy of Large Lipid Core Plaques at Culprit Sites in Patients With Acute ST-Segment Elevation Myocardial Infarction

OBJECTIVES This study sought to describe near-infrared spectroscopy (NIRS) findings of culprit lesions in ST-segment elevation myocardial infarction (STEMI). BACKGROUND Although autopsy studies demonstrate that most STEMI are caused by rupture of pre-existing lipid core plaque (LCP), it has not been possible to identify LCP in vivo. A novel intracoronary NIRS catheter has made it possible to detect LCP in patients. METHODS We performed NIRS within the culprit vessels of 20 patients with acute STEMI and compared the STEMI culprit findings to findings in nonculprit segments of the artery and to findings in autopsy control segments. Culprit and control segments were analyzed for the maximum lipid core burden index in a 4-mm length of artery (maxLCBI(4mm)). RESULTS MaxLCBI(4mm) 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]; p < 0.001) and 87-fold higher than in 279 coronary autopsy segments free of large LCP by histology (median [IQR]: 523 [445 to 821] vs. 6 [0 to 88]; p < 0.001).Within the STEMI culprit artery, NIRS accurately distinguished culprit from nonculprit segments (receiver-operating characteristic analysis area under the curve = 0.90). A threshold of maxLCBI(4mm) >400 distinguished STEMI culprit segments from specimens free of large LCP by histology (sensitivity: 85%, specificity: 98%). CONCLUSIONS The present study has demonstrated in vivo that a maxLCBI(4mm) >400, as detected by NIRS, is a signature of plaques causing STEMI.

Insights Into Echo-Attenuated Plaques, Echolucent Plaques, and Plaques With Spotty Calcification: Novel Findings From Comparisons Among Intravascular Ultrasound, Near-Infrared Spectroscopy, and Pathological Histology in 2,294 Human Coronary Artery Segments

OBJECTIVES Three intravascular ultrasound (IVUS) signatures have been associated with coronary artery disease instability: echo attenuation, an intraplaque echolucent zone, and spotty calcification. The aim of this study was to investigate the substrates responsible for these IVUS signatures in a relatively large series of post-mortem human coronary samples. BACKGROUND The exact mechanisms and pathological correlates underlying echo attenuation, an intraplaque echolucent zone, and spotty calcification remain poorly understood. METHODS IVUS was compared with near-infrared spectroscopic detection of lipid core plaque and histopathology in 2,294 vessel segments from 151 coronary specimens from 62 patients at necropsy using the modified American Heart Association classification. RESULTS IVUS detected echo-attenuated plaques in 18.3% of segments, echolucent plaques in 10.5% of segments, and spotty calcification in 14.4% of segments. Histopathologically, 91.4% of echo-attenuated plaques corresponded to either a fibroatheroma (FA) with a necrotic core (NC) or pathological intimal thickening with a lipid pool; almost all segments with superficial echo attenuation indicated the presence of an FA with an advanced NC. Echolucent plaques indicated the presence of a relatively smaller lipid or NC compared with echo-attenuated plaques (thickness: 0.51 mm [interquartile range (IQR): 0.35 to 0.64 mm] vs. 0.70 mm [IQR: 0.54 to 0.92 mm] [p < 0.001]; arc: 74.5° [IQR: 59.0° to 101.0°] vs. 90° [IQR: 70.0° to 112.0°] [p < 0.001]), although 82.8% of superficial echolucent zones indicated an NC-containing FA. IVUS spotty calcification, especially when superficial in location (72.6%), was often associated with an FA with calcium deposits and had smaller arcs of calcium in the setting of FA compared with fibrocalcific plaques (37.5° [IQR: 23.0° to 53.0°] vs. 59.0° [IQR: 46.0° to 69.0°]; p < 0.001). Comparisons between IVUS and near-infrared spectroscopy revealed that echo-attenuated plaques contained the highest probability of near-infrared spectroscopy-derived lipid core plaque, followed by echolucent plaques and spotty calcifications. CONCLUSIONS This study demonstrated that echo-attenuated plaque, especially superficial echo attenuation, was the most reliable IVUS signature for identifying a high-risk plaque (i.e., an FA containing a large NC).

Histopathologic Validation of the Intravascular Ultrasound Diagnosis of Calcified Coronary Artery Nodules

A calcified nodule is a type of potentially vulnerable plaque accounting for approximately 2% to 7% of coronary events. Because its intravascular ultrasound (IVUS) features have never been validated, the aim of this study was to assess the IVUS characteristics of calcified nodules in comparison to histopathology. IVUS was performed in 856 pathologic slices in 29 coronary arteries (11 left anterior descending, 5 left circumflex, and 13 right coronary arteries) in 18 autopsy hearts. Pathologic sections were analyzed every 2 mm; qualitative and quantitative findings of matched IVUS were analyzed. IVUS detected calcification in 285 frames; 17 (6.0%) were calcified nodules, and 268 (94.0%) were non-nodular calcium by histopathology. Two calcified nodules (11.8%) were solitary, and 15 (88.2%) were adjacent to non-nodular calcium. IVUS characteristics of calcified nodules were (1) a convex shape of the luminal surface (94.1% in calcified nodules vs 9.7% in non-nodular calcium, p <0.001), (2) a convex shape of the luminal side of calcium (100% vs 16.0%, p <0.001), (3) an irregular luminal surface (64.7% vs 11.6%, p <0.001), and (4) an irregular leading edge of calcium (88.2% vs 19.0%, p <0.001). Luminal area at the calcified nodule site was larger (6.2 ± 2.4 vs 4.3 ± 1.6 mm(2), p <0.001) and plaque burden less (57 ± 6% vs 68 ± 5%, p <0.001) than at the minimum luminal area site. In conclusion, calcified nodules have distinct IVUS features (irregular and convex luminal surface) permitting their prospective identification in vivo.

Large lipid-rich coronary plaques detected by near-infrared spectroscopy at non-stented sites in the target artery identify patients likely to experience future major adverse cardiovascular events

AIMS A recent study demonstrated that intracoronary near-infrared spectroscopy (NIRS) findings in non-target vessels are associated with major adverse cardiovascular and cerebrovascular events (MACCE). It is unknown whether NIRS findings at non-stented sites in target vessels are similarly associated with future MACCE. This study evaluated the association between large lipid-rich plaques (LRP) detected by NIRS at non-stented sites in a target artery and subsequent MACCE. METHODS AND RESULTS This study evaluated 121 consecutive registry patients undergoing NIRS imaging in a target artery. After excluding stented segments, target arteries were evaluated for a large LRP, defined as a maximum lipid core burden index in 4 mm (maxLCBI4 mm) ≥400. Excluding events in stented segments, Cox regression analysis was performed to evaluate for an association between a maxLCBI4 mm ≥400 and future MACCE, defined as all-cause mortality, non-fatal acute coronary syndrome, and cerebrovascular events. NIRS detected a maxLCBI4 mm ≥400 in a non-stented segment of the target artery in 17.4% of patients. The only baseline clinical variable marginally associated with MACCE was ejection fraction (HR 0.96, 95% CI 0.93-1.00, P = 0.054). A maxLCBI4 mm ≥400 in a non-stented segment at baseline was significantly associated with MACCE during follow-up (HR 10.2, 95% CI 3.4-30.6, P < 0.001). CONCLUSION Detection of large LRP by NIRS at non-stented sites in a target artery was associated with an increased risk of future MACCE. These findings support ongoing prospective studies to further evaluate the ability of NIRS to identify vulnerable patients.

Novel optical detection system for in vivo identification and localization of cervical intraepithelial neoplasia

A noncontact optical detection system is developed for the in vivo identification and localization of high-grade cervical intraepithelial neoplasia (CIN 2,3). Diagnostic scans of the entire human cervix are performed following acetic acid application employing three integrated optical measurements: laser-induced fluorescence spectroscopy, white light diffuse reflectance spectroscopy, and video imaging. Full cervical scans comprising 499 interrogation locations at 1-mm spatial resolution are completed in 12 s. Diffuse reflectance and fluorescence spectra with signal-to-noise ratios of better than 100-to-1 are collected between 360 and 720 nm in increments of 1 nm, with an inherent spectral resolution of 8 nm. Glare reduction and optical vignetting are handled with a novel illumination scheme and subsequent spectral arbitration algorithms. The system is designed and found to be well below acceptable safe optical exposure levels. Typical reproducibility across multiple systems is approximately 5%, providing reliable and accurate detection of in vivo cervical neoplasia in normal clinical use.

Near-Infrared Spectroscopy Enhances Intravascular Ultrasound Assessment of Vulnerable Coronary Plaque A Combined Pathological and In Vivo Study

Objectives—Pathological studies demonstrate the dual significance of plaque burden (PB) and lipid composition for mediating coronary plaque vulnerability. We evaluated relationships between intravascular ultrasound (IVUS)–derived PB and arterial remodeling with near-infrared spectroscopy (NIRS)–derived lipid content in ex vivo and in vivo human coronary arteries. Approach and Results—Ex vivo coronary NIRS and IVUS imaging was performed through blood in 116 coronary arteries of 51 autopsied hearts, followed by 2-mm block sectioning (n=2070) and histological grading according to modified American Heart Association criteria. Lesions were defined as the most heavily diseased 2-mm block per imaged artery on IVUS. IVUS-derived PB and NIRS-derived lipid core burden index (LCBI) of each block and lesion were analyzed. Block-level analysis demonstrated significant trends of increasing PB and LCBI across more complex atheroma (Ptrend <0.001 for both LCBI and PB). Lesion-based analyses demonstrated the highest LCBI and remodeling index within coronary fibroatheroma (Ptrend <0.001 and 0.02 versus all plaque groups, respectively). Prediction models demonstrated similar abilities of PB, LCBI, and remodeling index for discriminating fibroatheroma (c indices: 0.675, 0.712, and 0.672, respectively). A combined PB+LCBI analysis significantly improved fibroatheroma detection accuracy (c index 0.77, P=0.028 versus PB; net-reclassification index 43%, P=0.003), whereas further adding remodeling index did not (c index 0.80, P=0.27 versus PB+LCBI). In vivo comparisons of 43 age- and sex-matched patients (to the autopsy cohort) undergoing combined NIRS-IVUS coronary imaging yielded similar associations to those demonstrated ex vivo. Conclusions—Adding NIRS to conventional IVUS-derived PB imaging significantly improves the ability to detect more active, potentially vulnerable coronary atheroma.

Near-Infrared Spectroscopy Enhances Intravascular Ultrasound Assessment of Vulnerable Coronary Plaque

Objectives—Pathological studies demonstrate the dual significance of plaque burden (PB) and lipid composition for mediating coronary plaque vulnerability. We evaluated relationships between intravascular ultrasound (IVUS)–derived PB and arterial remodeling with near-infrared spectroscopy (NIRS)–derived lipid content in ex vivo and in vivo human coronary arteries. Approach and Results—Ex vivo coronary NIRS and IVUS imaging was performed through blood in 116 coronary arteries of 51 autopsied hearts, followed by 2-mm block sectioning (n=2070) and histological grading according to modified American Heart Association criteria. Lesions were defined as the most heavily diseased 2-mm block per imaged artery on IVUS. IVUS-derived PB and NIRS-derived lipid core burden index (LCBI) of each block and lesion were analyzed. Block-level analysis demonstrated significant trends of increasing PB and LCBI across more complex atheroma (Ptrend <0.001 for both LCBI and PB). Lesion-based analyses demonstrated the highest LCBI and remodeling index within coronary fibroatheroma (Ptrend <0.001 and 0.02 versus all plaque groups, respectively). Prediction models demonstrated similar abilities of PB, LCBI, and remodeling index for discriminating fibroatheroma (c indices: 0.675, 0.712, and 0.672, respectively). A combined PB+LCBI analysis significantly improved fibroatheroma detection accuracy (c index 0.77, P=0.028 versus PB; net-reclassification index 43%, P=0.003), whereas further adding remodeling index did not (c index 0.80, P=0.27 versus PB+LCBI). In vivo comparisons of 43 age- and sex-matched patients (to the autopsy cohort) undergoing combined NIRS-IVUS coronary imaging yielded similar associations to those demonstrated ex vivo. Conclusions—Adding NIRS to conventional IVUS-derived PB imaging significantly improves the ability to detect more active, potentially vulnerable coronary atheroma.

A catheter-based near-infrared scanning spectroscopy system for imaging lipid-rich plaques in human coronary arteries in vivo

Although heart disease remains the leading cause of death in the industrialized world, there is still no method, even under cardiac catheterization, to reliably identify those atherosclerotic lesions most likely to lead to heart attack and death. These lesions, which are often non-stenotic, are frequently comprised of a necrotic, lipid-rich core overlaid with a thin fibrous cap infiltrated with inflammatory cells. InfraReDx has developed a scanning, near-infrared, optical-fiber-based, spectroscopic cardiac catheter system capable of acquiring NIR reflectance spectra from coronary arteries through flowing blood under automated pullback and rotation in order to identify lipid-rich plaques (LRP). The scanning laser source and associated detection electronics produce a spectrum in 5 ms at a collection rate of 40 Hz, yielding thousands of spectra in a single pullback. The system console analyzes the spectral data with a chemometric model, producing a hyperspectral image (a Chemogram, see figure below) that identifies LRP encountered in the region interrogated by the system. We describe the system architecture and components, explain the experimental procedure by which the chemometric model was constructed from spectral data and histology-based reference information collected from autopsy hearts, and provide representative data from ongoing ex vivo and clinical studies.