Near-Infrared Spectroscopy Analysis of Coronary Chronic Total Occlusions

Abstract: Objective. To examine the presence and localization of lipid-core plaque (LCP) in coronary vessels with chronic total occlusions (CTOs) using near-infrared spectroscopy (NIRS). Methods. NIRS imaging was performed after guidewire crossing of the occlusion in 15 patients with CTOs. LCP was defined as ≥2 adjacent 2 mm yellow blocks on the block chemogram. We also measured the maximum lipid-core burden index (LCBI) in a 4 mm length of artery (maxLCBI4mm). Large LCP was defined as maxLCBI4mm ≥500. Results. Median patient age was 64 years (interquartile range [IQR], 61-67 years) and all patients were men with high prevalence of diabetes mellitus (64%) and prior coronary artery bypass graft surgery (27%). The CTO target vessel was the right coronary artery (46%), left anterior descending artery (27%), or circumflex artery (27%). Median occlusion length was 35 mm (IQR, 30-50 mm). LCP was present in 11 of 15 CTO vessels (73%) and a large LCP in 4 of 15 CTO vessels (27%). LCP was located at the proximal cap in 6 CTOs (55%), the CTO body in 6 CTOs (55%), and the distal cap in 2 CTOs (18%). The median overall LCBI and maxLCBI4mm were 145 (IQR, 79-243) and 415 (IQR, 267-505), respectively. All patients underwent successful stenting without any complications. The 12-month incidence of in-stent restenosis and target-lesion revascularization was 25%, and all patients who developed restenosis had an LCP at baseline. Conclusions. LCPs are commonly encountered in coronary CTO vessels, suggesting an active intraplaque atherosclerotic process. The impact of LCP on postintervention outcomes requires further study. 

J INVASIVE CARDIOL 2016;28(12):485-488.

Key words: Chronic total occlusions, near-infrared spectroscopy, percutaneous coronary intervention, lipid-core burden index

Coronary chronic total occlusions (CTOs) are lesions with Thrombolysis in Myocardial Infarction (TIMI) 0 flow and occlusion duration of ≥3 months.¹ Coronary CTOs are common, with a prevalence between 13.3% and 52.0% among patients with coronary artery disease who undergo coronary angiography.^2-6 CTO percutaneous coronary interventions (PCIs) represent 3.8% of all PCIs performed for stable coronary artery disease in the United States. Overall success rates remain low (59%),⁷ although approximately 90% success rates can be achieved at experienced centers using contemporary techniques and equipment.⁸

Several autopsy studies have provided insights on the composition of CTO lesions,^9-11 but there are few in vivo studies.¹² Near-infrared spectroscopy (NIRS) is a novel catheter-based technique capable of identifying lipid-core plaques (LCPs) within the coronary artery wall.¹³ NIRS is combined with intravascular ultrasound (IVUS), allowing simultaneous assessment of structure and composition. The goal of the present study was to examine the findings of coronary CTO imaging using NIRS-IVUS. 

Methods

Patients. Patients who underwent NIRS-IVUS imaging after CTO crossing between June 2012 and May 2015 at our institution were included in the present study. NIRS-IVUS of the CTO vessel was performed after guidewire crossing or after predilation with a 1.5 mm balloon if the catheter could not cross the occlusion, at the discretion of the operator. Patients were enrolled in the Lipid cORe Plaque Association With CLinical Events: a Near-InfraRed Spectroscopy Study (ORACLE-NIRS; NCT02265146) and the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS CTO; NCT02061436).

Quantitative coronary angiography. Coronary angiograms were obtained in standard views after intracoronary administration of nitroglycerin and using dual injection in all cases. The projection that best showed the occlusion was used for all analyses. All analyses were performed at the VA North Texas Health Care System core angiographic laboratory using a computer-based algorithm (CAAS II; Pie Medical). The minimal luminal diameter (MLD) and the nearest normal reference diameter (RVD) were measured in millimeters by using the catheter as a scaling factor. Percentage of stenosis was calculated as 100 (1 – MLD/RVD). The length of the occlusion was measured on the angiograms obtained using dual injection. The complexity of the CTO lesions was assessed by calculating the J-CTO score, as previously described.¹⁴

NIRS and IVUS analyses. Imaging was performed after intracoronary administration of 200 µg nitroglycerin. The NIRS-IVUS catheter (TVC Imaging System; Infraredx) was advanced beyond the occlusion, and motorized pullback was performed at 0.5 mm/s. 

The NIRS images were analyzed as previously described.^16-18 NIRS images were considered uninterpretable and excluded from further analysis if the corresponding block chemogram (a summary of the NIRS values in a 2 mm length of pullback) was black in color, indicating the absence of reliable data. The total lesion lipid-core burden index (LCBI) and maximal LCBI over any 4 mm segment (maxLCBI4mm) were automatically calculated.¹⁸ Raw spectroscopic data are converted into a probability of LCP on a red-to-yellow color scale, with red representing low probability of lipid and yellow representing high probability. LCBI represents the proportion of yellow pixels (lipid probability >0.6) in the plaque, reported on a scale of 0 to 1000 (signifying 0% to 100% lipid). The number of yellow pixels every 0.1 mm was determined by the automated software and summed over each possible 4 mm-long axial segment to determine the maxLCBI4mm.

We identified the proximal and distal CTO cap using vessel landmarks. We then compared the composition of the proximal reference segment, CTO segment, and distal reference segment.

Statistical analyses. Continuous parameters were reported as mean ± standard deviation or median (interquartile range) and compared with one-way ANOVA or the Wilcoxon rank-sum test, as appropriate. Discrete parameters were reported as percentages (%) and were compared with the Pearson chi-square test or the Fisher’s exact test, as appropriate. All statistical analyses were performed with JMP 11 (SAS Institute). 

Results

 Clinical and angiographic characteristics. During the study period, 15 patients underwent NIRS-IVUS imaging after CTO crossing and were included in the present study. The baseline characteristics of the study patients are shown in Table 1. Median age was 64 years (IQR, 61-67 years) and all patients were men with high prevalence of diabetes mellitus (64%), hyperlipidemia (87%), prior myocardial infarction (47%), prior percutaneous coronary intervention (33%), and prior coronary artery bypass graft surgery (27%). The CTO target vessel was the right coronary artery (46%), left anterior descending artery (27%), or circumflex artery (27%). Median occlusion length was 35 mm (IQR, 30-50 mm). 

NIRS and IVUS findings. Indications for NIRS-IVUS included resolving proximal cap ambiguity (6.7%), assisting with guidewire crossing (13.3%) or the reverse controlled antegrade and retrograde tracking and dissection (reverse CART) technique (13.3%), stent sizing (40%), and stent optimization (46.7%). 

LCP was present in 11 of 15 CTO vessels (73%) and a large LCP in 4 of 15 CTO vessels (27%). The LCP was located in the proximal reference segment in 6 patients (55%), the CTO body in 6 patients (55%), and the distal reference segment in 2 patients (18%) (Table 2). The median LCBI and maxLCBI4mm overall were 145 (IQR, 79-243) and 415 (IQR, 267-505), respectively. Median maxLCBI4mm in the left anterior descending artery, circumflex, and right coronary artery was 386 (IQR, 299-470), 292 (IQR, 267-415), and 498 (IQR, 210-684), respectively (P=.44). 

Follow-up. All patients underwent successful stenting without any complications. During a median follow-up of 8 months (IQR, 4-15 months), 1 patient died of cardiac arrest at an outside hospital, 3 patients (all of whom had LCP within the CTO segment) developed restenosis and underwent PCI of the target lesion (12-month incidence of target-lesion revascularization was 25%), and 1 patient underwent coronary artery bypass graft surgery due to progression of disease in a non-target vessel. 

Discussion

To the best of our knowledge, this is the first study to perform in vivo imaging of coronary CTO vessels using NIRS-IVUS. We found that LCPs were common in CTOs (in 73% of studied CTO arteries), especially within the proximal reference and within the occlusion segment.

Several histopathology studies^10-12 have shown that CTOs are composed predominantly of fibrous tissue, atheromatic plaque, and calcification. Katsuragawa et al¹¹ demonstrated that almost 65% of CTO lesions contained extensive fibrocalcific plaque, with collagen and calcium occupying >50% of the plaque, whereas only 11% of CTOs were composed mainly of cholesterol-laden plaque with foam cells and loose fibrous tissue. Srivatsa et al showed that with advancing occlusion age, plaque composition changes from lipid-laden to fibrocalcific.¹⁰

Guo et al performed virtual histology IVUS in 50 CTO lesions and found fibroatheroma in 84% of the studied lesions (83% of which were within the entire length of the CTO),¹² which is similar to the 73% prevalence of LCP reported in our study. The frequent presence of LCPs in coronary CTOs, particularly proximal and within the CTO body lesion, could suggest an active intraplaque atherosclerotic process, which might have an impact on postprocedural outcomes. In addition, the high prevalence of LCP implies that most CTOs evolve from acute coronary syndrome lesions, most likely through plaque rupture and subsequent thrombotic occlusion.¹²

Stenting LCP may be associated with increased risk for acute complications (such as distal embolization) and chronic complications (such as in-stent restenosis and stent thrombosis).^19-22 In our study, 1 in 5 patients developed in-stent restenosis during a median follow-up of 8 months, all of whom had LCP in the CTO segment during baseline imaging. CTOs may be at increased risk for in-stent restenosis, even after drug-eluting stent implantation,^23,24 and use of LCP could help identify occlusions at high risk for restenosis.

Apart from CTOs, LCPs are frequently encountered in non-CTO lesions, especially in patients with acute coronary syndromes. Madder et al¹⁶ identified large LCPs in 14 of 20 patients presenting with ST-segment elevation acute myocardial infarction (STEMI). Goldstein et al¹⁸ examined 62 patients from the COLOR registry (patients presenting with STEMI were excluded), reporting that large LCPs were present in 14 out of 62 patients (23%), with large LCPs being independently associated with increased risk for periprocedural MI. Similar results were reported by Raghunathan et al.²⁵ 

Study limitations. Our study is limited by the relatively small sample size and single-center design, which limits the power to detect association of baseline CTO characteristics and subsequent clinical outcomes. Some lesions required ballooning for delivery of the NIRS-IVUS catheter that may have modified the lesion. Moreover, some lesions were crossed using subintimal techniques, which could result in underestimation of the amount and extent of LCP. Only lesions successfully crossed with a guidewire were included in the present study, and it is possible that CTOs in which guidewire crossing fails have different characteristics, such as higher prevalence of calcification and tortuosity and longer length.

Conclusion

Lipid-core plaques are commonly encountered in coronary CTOs, suggesting an active intraplaque atherosclerotic process. Further study is needed to examine the impact of LCP on short-term and long-term outcomes after CTO-PCI.

References

1.     Brilakis ES. Manual of Coronary Chronic Total Occlusion Interventions. A Step-By-Step Approach. Waltham, MA: Elsevier; 2013.

2.     Fefer P, Knudtson ML, Cheema AN, et al. Current perspectives on coronary chronic total occlusions: the Canadian Multicenter Chronic Total Occlusions Registry. J Am Coll Cardiol. 2012;59:991-997.

3.     Christofferson RD, Lehmann KG, Martin GV, Every N, Caldwell JH, Kapadia SR. Effect of chronic total coronary occlusion on treatment strategy. Am J Cardiol. 2005;95:1088-1091.

4.     Werner GS, Gitt AK, Zeymer U, et al. Chronic total coronary occlusions in patients with stable angina pectoris: impact on therapy and outcome in present day clinical practice. Clin Res Cardiol. 2009;98:435-441.

5.    Jeroudi OM, Alomar ME, Michael TT, et al. Prevalence and management of coronary chronic total occlusions in a tertiary veterans affairs hospital. Catheter Cardiovasc Interv. 2014;84:637-643.

6.     Tomasello SD, Boukhris M, Giubilato S, et al. Management strategies in patients affected by chronic total occlusions: results from the Italian Registry of Chronic Total Occlusions. Eur Heart J. 2015;36:3189-3198. Epub 2015 Sep 2.

7.     Brilakis ES, Banerjee S, Karmpaliotis D, et al. Procedural outcomes of chronic total occlusion percutaneous coronary intervention: a report from the NCDR (National Cardiovascular Data Registry). JACC Cardiovasc Interv. 2015;8:245-253.

8.     Christopoulos G, Karmpaliotis D, Alaswad K, et al. Application and outcomes of a hybrid approach to chronic total occlusion percutaneous coronary intervention in a contemporary multicenter US registry. Int J Cardiol. 2015;198:222-228.

9.     Sakakura K, Nakano M, Otsuka F, et al. Comparison of pathology of chronic total occlusion with and without coronary artery bypass graft. Eur Heart J. 2014;35:1683-1693.

10.     Srivatsa SS, Edwards WD, Boos CM, et al. Histologic correlates of angiographic chronic total coronary artery occlusions: influence of occlusion duration on neovascular channel patterns and intimal plaque composition. J Am Coll Cardiol. 1997;29:955-963.

11.     Katsuragawa M, Fujiwara H, Miyamae M, Sasayama S. Histologic studies in percutaneous transluminal coronary angioplasty for chronic total occlusion: comparison of tapering and abrupt types of occlusion and short and long occluded segments. J Am Coll Cardiol. 1993;21:604-611.

12.     Guo J, Maehara A, Mintz GS, et al. A virtual histology intravascular ultrasound analysis of coronary chronic total occlusions. Catheter Cardiovasc Interv. 2013;81:464-470.

13.     Oemrawsingh RM, Cheng JM, Garcia-Garcia HM, et al. Near-infrared spectroscopy predicts cardiovascular outcome in patients with coronary artery disease. J Am Coll Cardiol. 2014;64:2510-2518.

14.     Morino Y, Abe M, Morimoto T, et al. Predicting successful guidewire crossing through chronic total occlusion of native coronary lesions within 30 minutes: the J-CTO (Multicenter CTO Registry in Japan) score as a difficulty grading and time assessment tool. JACC Cardiovasc Interv. 2011;4:213-221.

15.     Mintz GS, Nissen SE, Anderson WD, et al. American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS): a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents developed in collaboration with the European Society of Cardiology endorsed by the Society of Cardiac Angiography and Interventions. J Am Coll Cardiol. 2001;37:1478-1492.

16.     Madder RD, Goldstein JA, Madden SP, et al. Detection by near-infrared spectroscopy of large lipid core plaques at culprit sites in patients with acute ST-segment elevation myocardial infarction. JACC Cardiovasc Interv. 2013;6:838-846.

17.     Stone GW, Maehara A, Muller JE, et al. Plaque characterization to inform the prediction and prevention of periprocedural myocardial infarction during percutaneous coronary intervention: the CANARY trial (Coronary Assessment by Near-infrared of Atherosclerotic Rupture-prone Yellow). JACC Cardiovasc Interv. 2015;8:927-936.

18.     Goldstein JA, Maini B, Dixon SR, et al. Detection of lipid-core plaques by intracoronary near-infrared spectroscopy identifies high risk of periprocedural myocardial infarction. Circ Cardiovasc Interv. 2011;4:429-437.

19.     Farb A, Sangiorgi G, Carter AJ, et al. Pathology of acute and chronic coronary stenting in humans. Circulation. 1999;99:44-52.

20.     Sakhuja R, Suh WM, Jaffer FA, Jang IK. Residual thrombogenic substrate after rupture of a lipid-rich plaque: possible mechanism of acute stent thrombosis? Circulation. 2010;122:2349-2350.

21.     Papayannis AC, Abdel-Karim AR, Mahmood A, et al. Association of coronary lipid core plaque with intrastent thrombus formation: a near-infrared spectroscopy and optical coherence tomography study. Catheter Cardiovasc Interv. 2013;81:488-493.

22.     Brilakis ES, Abdel-Karim AR, Papayannis AC, et al. Embolic protection device utilization during stenting of native coronary artery lesions with large lipid core plaques as detected by near-infrared spectroscopy. Catheter Cardiovasc Interv. 2012;80:1157-1162.

23.     Kotsia A, Navara R, Michael TT, et al. The angiographic evaluation of the everolimus-eluting stent in chronic total occlusion (ACE-CTO) study. J Invasive Cardiol. 2015;27:393-400.

24.     Lanka V, Patel VG, Saeed B, et al. Outcomes with first- versus second-generation drug-eluting stents in coronary chronic total occlusions (CTOs): a systematic review and meta-analysis. J Invasive Cardiol. 2014;26:304-310.

25.     Raghunathan D, Abdel-Karim AR, Papayannis AC, et al. Relation between the presence and extent of coronary lipid core plaques detected by near-infrared spectroscopy with postpercutaneous coronary intervention myocardial infarction. Am J Cardiol. 2011;107:1613-1618.

26.    Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap) – a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377-381.

From the VA North Texas Healthcare System and UT Southwestern Medical Center, Dallas, Texas.

Funding: The Lipid cORe Plaque Association With CLinical Events: a Near-InfraRed Spectroscopy Study (ORACLE-NIRS) registry is supported by a grant from InfraRedx (Burlington, Massachusetts). For the Prospective Global Registry for the Study of Chronic Total Occlusion Intervention (PROGRESS CTO, NCT02061436), study data were collected and managed using REDCap electronic data capture tools²⁶ hosted at University of Texas Southwestern Medical Center.REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for importing data from external sources. The study was also supported by CTSA NIH Grant UL 1-RR024982.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. BV Rangan reports grant support from Infraredx and Spectranetics. Dr Banerjee reports research grants from Gilead and the Medicines Company; consultant/speaker honoraria from Covidien and Medtronic; ownership in MDCare Global (spouse); intellectual property in HygeiaTel. Dr Brilakis reports consulting/speaker honoraria from Abbott Vascular, Asahi Intecc, Boston Scientific, Elsevier, Somahlution, St Jude Medical, and Terumo; research support from Boston Scientific and InfraRedx; spouse is employee of Medtronic. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted March 10, 2016, provisional acceptance given May 3, 2016, final version accepted June 20, 2016.

Address for correspondence: Emmanouil S. Brilakis, MD, PhD, Minneapolis Heart Institute, 920 E. 28th Street #300, Minneapolis, MN 55407. Email: esbrilakis@gmail.com