Accepted Manuscript. In vivo vulnerability grading system of plaques causing acute coronary syndromes: An intravascular imaging study

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1 Accepted Manuscript In vivo vulnerability grading system of plaques causing acute coronary syndromes: An intravascular imaging study Francesco Prati, Laura Gatto, Enrico Romagnoli, Ugo Limbruno, Massimo Fineschi, Valeria Marco, Mario Albertucci, Corrado Tamburino, Filippo Crea, Fernando Alfonso, Eloisa Arbustini PII: S (18) DOI: doi: /j.ijcard Reference: IJCA To appear in: International Journal of Cardiology Received date: 12 March 2018 Revised date: 5 June 2018 Accepted date: 29 June 2018 Please cite this article as: Francesco Prati, Laura Gatto, Enrico Romagnoli, Ugo Limbruno, Massimo Fineschi, Valeria Marco, Mario Albertucci, Corrado Tamburino, Filippo Crea, Fernando Alfonso, Eloisa Arbustini, In vivo vulnerability grading system of plaques causing acute coronary syndromes: An intravascular imaging study. Ijca (2018), doi: /j.ijcard This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 In vivo vulnerability grading system of plaques causing acute coronary syndromes: an intravascular imaging study. Francesco Prati 1-2, MD; Laura Gatto 1-2, MD; Enrico Romagnoli 1-2, MD, PhD; Ugo Limbruno 3, MD; Massimo Fineschi 4, MD; Valeria Marco 2, RN; Mario Albertucci 2, MD; Corrado Tamburino 5, MD; Filippo Crea 6, MD; Fernando Alfonso 7, MD; Eloisa Arbustini 8, MD. 1. Cardiology Unit, San Giovanni Addolorata Hospital, Rome, Italy 2. C.L.I. Foundation, Rome, Italy 3. Cardiology, Misericordia Hospital, Grosseto, Italy 4. Azienda Ospedaliera Universitaria Senese, Siena, Italy 5. Cardio-Thoracic-Vascular Department, Ferrarotto Hospital, University of Catania, Italy 6. Catholic University of Sacred Heart, Rome, Italy 7. Servicio de Cardiología, Hospital Universitario de La Princesa, Madrid, Spain 8. IRCCS Fondazione Policlinico San Matteo, Pavia, Italy ACKNOWLEDGMENTS: This study has been supported by a grant from the Centro per la Lotta contro l Infarto - CLI -Fondazione Onlus, which receives no industry funding. Dr Prati has served as consultant for Abbot-St.Jude and Amgen. The other authors have no conflict of interest to disclose. bias the the

3 Key Words: Optical Coherence Tomography, Intra-Vascular Ultrasound-Near Infrared Spectroscopy, Vulnerable plaque, Acute Coronary Syndrome Corresponding author: Dr. Francesco Prati, Cardiology Unit, San Giovanni-Addolorata Hospital, Via Amba Aradam 9, Rome, Italy. Phone: , Fax bias the the

4 STRUCTURED ABSTRACT Background: Autopsy studies shed light on the interplay between fatal acute coronary syndromes (ACS) and features of plaque vulnerability. This is a prospective pilot study designed for generating a new in vivo imaging grading system of plaque vulnerability. Methods: We studied 87 coronary vessels in 63 consecutive patients: 48 with Acute Coronary Syndrome (ACS) and 15 with stable coronary artery disease using IntraVascular-Ultrasound Near- Infrared-Spectroscopy (IVUS-NIRS) and Optical Coherence Tomography (OCT). We identified 99 lesions: 21 were the ACS culprit lesions (18 ulcerations and 3 with intact fibrous cap), 78 were nonculprit lesions including plaques located in the same ACS culprit vessel (N12), plaques located in a non-culprit vessel in patients with ACS (28) and target lesions of stable patients (N 38). A second analysis focused on lipid plaques, comparing the 18 ACS culprit ulcerated lesions and the 55 nonculprit lesions. Results: The co-presence of the following three features of vulnerability [Minimal Luminal Area (MLA) <4mm 2, Fibrous Cap Thickness (FCT)<75µm and superficial macrophages] was by far more frequent in ACS culprit lesions than in controls (OR 40.6 for all lesions and OR 45.7 for bias the the

5 ulcerated culprit lesions only). The triple-feature OCT grading identified vulnerable plaques with a much higher accuracy than that obtained applying each single feature of vulnerability. Conclusions: The co-presence of the 3 OCT features of vulnerability (MLA<4 mm 2, FCT<75µm and superficial macrophages) identifies culprit ACS lesions with a very high odd ratio. This finding could set the basis for a new OCT vulnerability grading system including superficial macrophages. Key Words: Optical Coherence Tomography, Intra-Vascular Ultrasound-Near Infrared Spectroscopy, Vulnerable plaque, Acute Coronary Syndrome INTRODUCTION The search for vulnerable atherosclerotic lesions in the coronary tree is a valid approach to scrutinize high-risk patients, providing a complementary approach to the Framingham score [1-3]. Previous studies carried on with non-invasive and invasive imaging modalities corroborate this concept [4-6]. bias the the

6 Postmortem and intracoronary imaging studies showed that plaque rupture is the most common mechanism of acute coronary syndromes (ACS), being responsible for over 70% of events. Narula and coll. clarified the interplay between the different features of vulnerability and fatal events, showing that plaques causing ACS are characterized by a large necrotic core with a thin overlying fibrous cap (less than 70 µm), local inflammation and lumen narrowing. Such variables were less common in patients with the so-called vulnerable plaque that did not cause cardiac events [6]. However, such findings, including the search of local inflammation, have not been fully validated in vivo applying imaging modalities. In this study, we tested the possibility of generating an intracoronary imaging grading of plaque vulnerability based on data provided by the sequential use of Frequency Domain-Optical Coherence Tomography (FD-OCT) and Intra-Vascular Ultrasound-Near Infrared Spectroscopy (IVUS-NIRS) in a series of patients with and without ACS. METHODS Study design and patients population We enrolled 63 consecutive consenting patients who underwent percutaneous coronary intervention (PCI) in the period comprised between June and December 2016 for ACS [ST elevation myocardial bias the the

7 infarction (STEMI), non-st elevation myocardial infarction (NSTEMI) or unstable angina] [N 48 patients] or stable coronary artery disease (CAD) [N 15 patients]. Standard definitions of STEMI and NSTEMI were applied [7]. All patients underwent a comprehensive pre-intervention assessment with intra-coronary imaging modalities: FD-OCT and IVUS-NIRS. The local ethical board approved the project, and all patients provided written informed consent for the index procedure, and anonymous data management. The study protocol conforms to the ethical guidelines of the Declaration of Helsinki. This work was supported by the Centro per la Lotta contro l Infarto- CLI Fondazione Onlus (Rome, Italy) and authors were responsible for the design, conduct, and final contents of this study. The present work was intended as pilot study for a large multicentre registry on plaque vulnerability (Relationship between coronary plaque morphology of the left anterior descending artery and long term clinical outcome: the CLIMA study) (Trial.GOV NCT ). We evaluated both culprit and non-culprit plaques of patients with ACS and target artery of patients with stable CAD (Figure 1). We generated an intracoronary imaging-based grading of plaque vulnerability by combining different imaging features that can be explored with OCT and/or IVUS/NIRS: 1) Minimal Lumen Area (MLA) <4.0 mm 2 [7-9] 2) Thin, <75 microns, Fibrous Cap Thickness (FCT) at OCT (this cut-off value was based on histopathology and OCT data relating bias the the

8 ACS to the presence of a FCT comprised between 50 and 90 µm) [4,5,10-12] 3) presence of superficial macrophages detected by OCT at lesion site (defined as distance from lumen <80 µm) [5,11,12]; 4) Lipid Arc >90 at IVUS-NIRS[13,14]; 5) Plaque Burden >70% at IVUS [5,6]; 6) Lipid Core Burden Index (LCBI) reg* > 400 at IVUS/NIRS [15]. Demographic data and procedural details are shown in the table 1 supplementary. We enrolled patients without contraindications to intravascular imaging assessment (e.g. ostial plaques or extreme vessel tortuosity). The choice to perform an intracoronary vessel assessment by OCT and NIRS-IVUS was left to operator s discretion; this might be considered a study bias. IVUS-NIRS and OCT image acquisition Unfractionated heparin was administrated during PCI, with a target activated clotting time of >250 seconds. A mm guidewire was placed distally in the target vessel tract and an intracoronary injection of 200 mg of nitroglycerin was given prior to IVUS-NIRS and OCT pullbacks. A 3.2-Fr IVUS-NIRS catheter (LipiScan- IVUS, InfraRedx, Burlington, MA, USA) was first employed to interrogate the target artery. Image acquisition was performed by a motorized catheter pullback at a speed of 0.5 mm/s and 240 rpm in all studied segments. The system performed 1,000 chemical bias the the

9 measurements per 12.5 mm, in which each measurement interrogated 1 to 2 mm 2 of vessel wall from a depth of approximately 1 mm in the direction from the luminal surface toward the adventitia. Areas of the artery with spectral characteristics of a lipid core were displayed in yellow within the image map, called a chemogram [15]. Subsequently, FD-OCT images were obtained in the same coronary segment, using a commercially available system (Dragonfly; St Jude Medical, Westford, MA, USA) at a pullback speed of 20 mm/s. During image acquisition, coronary blood flow was replaced by continuous flushing of contrast media directly from the guiding catheter at a rate of 4 ml/s for the left system and 3 ml/s for the right coronary artery, using an automated power injector, in order to create a virtually blood-free environment [12]. The culprit lesion was identified on the basis of the findings by the coronary angiogram as well as the ECG [9,10]. To guarantee an optimal acquisition with both imaging techniques without delay in revascularization time (e.g. occluded culprit vessel), target lesions were treated with a gentle predilation with undersized (1.5 mm) compliant balloons in case of severe coronary narrowing or with thrombectomy in ACS patients with large thrombus burden. In all cases imaging acquisition was performed only after stable and valid anterograde coronary flow restoration. Acquired segments were located in the proximal coronary segments and had a minimum length of 50 mm. bias the the

10 Analysis and Matching of IVUS-NIRS and OCT images Both IVUS-NIRS and OCT images were digitally stored and analysed off-line by two independent investigators (F.P. and V.M.) at the Euroimage Research Core laboratory. Core laboratory personnel were blinded to all patient clinical data. Readers matched IVUS-NIRS and OCT images applying a validated methodology [16-18]. Briefly, matching was carried out taking into account the acquisition speed of the two image modalities, the take off of side branch and the lumen morphology of paired cross sections. A necrotic lipid core was defined as lower signal density region with heterogeneous back-scattering and poorly delineated borders [11,12]. The culprit lesion was classified as ruptured or intact cap (erosion) and the presence of thrombus was reported. Plaque rupture was defined as the presence of fibrous cap discontinuity leading to a communication between the inner (necrotic) core of the plaque and the lumen, with or without the presence of a flap [11,12]. Erosion was defined by the presence of intracoronary thrombus layered on the luminal surface of the plaque in the absence of detectable signs of underlying fibrous cap rupture [11,12]. Thrombus was defined as an intraluminal irregular mass adherent to or protruding from the plaque. Given that massive thrombi may impair the assessment of underlying structures due to the limited depth penetration of OCT laser light (approximately 1.5 mm) or the high backscattering with signal free shadowing appearance, respectively, each OCT cross-sections acquired along the entire bias the the

11 longitudinal extension of the coronary segment with thrombus were reviewed (for sites where vessel wall and plaque morphology could be assessed) [11,12]. For each target coronary plaque, we assessed the following OCT features: 1) the cross section with the MLA; 2) the minimum FCT in presence of lipid components and measured as the average of three measurements obtained in the same cross-section [8]; 3) the presence and localization of macrophage clusters addressed by means of a validated two-step algorithm using an OCT-derived tissue property software [18]; and 4) presence of intracoronary thrombus in presence of ruptured fibrous cap (ulceration) or intact fibrous cap [11,12]. In the same coronary plaque, the following measurements were obtained with IVUS-NIRS: 1) MLA, 2) Vessel Area; 3) Plaque burden (%); 4) NIRS-defined lipid pool arch that was calculated using the colour coded rim chemogram surrounding the grey IVUS image [13]. Furthermore, NIRS was used to measure the LCBI at the lesion site (within a 4 mm length). Statistical analysis Continuous variables are presented as mean (± standard deviation) or median (1st-3rd quartile) in case of normal or skewed distribution and compared using Student-t or Mann-Whitney U, respectively. Categorical variables are presented as counts or percentages and compared with χ2 or bias the the

12 Fisher exact test when appropriate. The standard univariate Mantel-Haenszel method was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for evaluation of the association between plaque vulnerability parameters and incidence of acute local thrombosis. A two tailed, p- value <0.05 was established as the level of statistical significance for all tests. All statistical analyses were carried out using SPSS-PASW 22.0 (IBM, Armonk, NY, USA). RESULTS The demographic and clinical characteristics of the studied population are shown in table 1 supplementary. Forty-eight patients out of 63 were admitted to our institution for ACS (17 STEMI, 24 NSTEMI and 7 Unstable Angina), while the remaining 15 patients had stable CAD. Procedures were done within 6 hours in presence of STEMI and within 24 hours in presence of NSTEMI or unstable angina. The target lesions were treated with undersized (1.5 mm) compliant balloons in 4 cases (19.0%) in the culprit group and 20 cases (25.6%) in the non-culprit group. Thrombus aspiration was performed only in 2 cases (9.5%) of the culprit group. IVUS-NIRS and OCT were successfully performed in 87 vessels with no complication directly related to the imaging acquisition phase. We identified 99 lesions and compared the 21 target bias the the

13 lesions responsible for ACS with the 78 non-culprit lesions, including plaques in stable cases (N 38), plaques located in the target artery of patients with ACS (N 12) and in non-target arteries of patients with ACS (N 28) (Figure 1). All the explored OCT features consistent with plaque vulnerability, including superficial macrophages, were significantly more common in plaques with thrombosis (group 1) (Table 1). On the other hand the IVUS-NIRS analysis reported a significant difference in culprit lesion only for the incidence of lipid arc >90 (Table 1 and 2). Table 2 supplementary focuses on plaques with lipid components. When comparing lipid plaques with cap rupture and thrombosis vs. those without rupture and thrombosis, the univariate analysis confirmed OCT results obtained in the overall lesion population, whilst presence of lipid arc >90 at IVUS-NIRS lost predictive value (Table 2 supplementary). The co-presence of the three following features of vulnerability in the same lesion (MLA<4 mm 2, FCT <75 µm and superficial inflammatory cells) was by far more frequent in the plaques with acute local thrombosis than in controls (OR 40.6) (table 2) (Figures 1 and 2 supplementary). The figure was even higher when lipid lesions with rupture and thrombosis were compared to non ruptured lipid lesions (OR 45.7) (table 3 supplementary). The between group OR for the simultaneous presence of these three variables was much greater than that of the single or the double variable bias the the

14 combinations (Figure 2). The addition of a forth variable (lipid arc >90 ) to the triple vulnerability grading did not further improve the between group OR. Interestingly, we observed a not significant trend to higher systemic inflammatory marker (i.e. C- reactive protein) in the culprit lesion group when compared to non-culprit one (0.37 [ ] mg/dl vs [0.1-08] mg/dl, p= 0.935). DISCUSSION The major findings of the present study are the following: 1. The new imaging grading based on the presence of three features of plaque vulnerability (including superficial macrophages), all detectable by OCT, identifies culprit ACS lesions with a very high odd ratio). 2. The triple OCT grading identifies vulnerable plaques with a much higher accuracy than that obtained applying single features of vulnerability. Past pathological studies offered a comprehensive insight into plaque vulnerability demonstrating that lesions with large superficial lipid pools covered with a thin FCT and a concomitant lumen area reduction are at risk of coronary events [19]. More recently, pathologists added new evidences, bias the the

15 emphasizing the role of local inflammation. The fact that coronary artery inflammation has a major role in promoting ACS is a well-known concept that was brought to the attention of clinicians over two decades ago [20]. Narula and coll. [4] showed that vulnerable plaques causing fatal ACS were complicated by a more intense local inflammation as compared to a second group of eventless vulnerable thin-cap fibro-athermanous plaques, and a third group of non-vulnerable, stable plaques. The extent of local inflammation at the culprit site was about two times and ten times higher as compared to vulnerable and stable sites, respectively. To our knowledge these pathologic findings have not yet been replicated in vivo. We first validated in vivo these findings applying a complex imaging modality based on sequential use of OCT and IVUS-NIRS. Such combination accurately diagnosed the structure of the plaque with ulceration at the culprit site that was found in 86% of cases, a higher figure than that found in previous histology studies [4,19]. The use of a dedicated grading A key point of the study is the application of a composite end-point of vulnerability. The triple grading including MLA <4 mm 2, FCT <75 µm and presence of superficial macrophages well characterize culprit ulcerated ACS plaques. Such composite end-point was detected in 61.9 % of all ACS culprit plaques and in 72.2 % of ACS culprit plaques with ulceration, with OR of 40.6 and bias the the

16 45.7, respectively. The triple grading (Table 2 and table 3 supplementary, Figure 2) was more accurate than each single or double combination of such vulnerability features. For instance, the between group OR for FCT <75 µm, that was the most accurate single predictor of vulnerability, was about one half of the triple grading OR. The amount of lipids does not seem to add a predictive value comparable to that of FCT, MLA reduction, and presence of cap inflammation. In fact, large amount of lipids is common in eventless plaques. It is plausible that a thin FCT and inflammations are key elements contributing to plaque rupture and exposing thrombogenic substrates to the blood stream. Once the cap breaks, the lipid core is exposed to blood flow: the necrotic lipid core and the fragmented collagen are the ideal substrates for the immediate formation of the thrombus, and a reduced lumen area is a prerequisite for further vessel occlusion. In this sequence of ominous events that cause thrombosis in ruptured plaques, lipids must be present but their quantity does not seem to be of utmost importance. In-fact when we added the circumferential arc of lipids as a forth variable to the triple grading we did not improve our model. Role of superficial macrophages bias the the

17 The identification of macrophages with intravascular imaging is a key issue. The ability of OCT to identify macrophages has been a debated issue in the last ten years. Tearney et al. [21] and, more recently, Di Vito et al. [18] showed that it is possible to identify, with good accuracy, clusters of macrophages by applying dedicated software (Figure 3 supplementary). The novelty of the current study is that the presence of macrophages is one of the three variables that enter the vulnerability OCT grading. We also find intriguing the fact that a superficial location of macrophages has a more relevant impact on plaque vulnerability than presence of macrophages per se. This was an expected finding because superficial cap inflammation can cause degradation of the extra cellular components of the fibrous cap, leading to its weakening, thinning and therefore favouring the cap rupture. The incorporation of superficial macrophages in a new vulnerability grading seems, therefore, important. Combined use of imaging modalities To provide a comprehensive view of coronary plaques we sequentially used two complementary imaging modalities (OCT and IVUS-NIRS). Applying a very accurate matching process OCT gives a unique view of the superficial components of the plaque, enabling assessment of macrophages and a precise quantitative assessment of MLA and FCT. On the other hand IVUS-NIRS can detail the bias the the

18 deep plaque morphology: it adds the quantification of the plaque burden and the lipid pool extension by calculating the lipid pool index and lipid arc at the lesion site. Consistently with previous data [15], they were higher in the ACS culprit lesions than in stable plaques. Clinical implications A vulnerability grading based on OCT assessment is a promising tool for improving stratification of clinical outcome in secondary prevention. Based on these preliminary data, the OCT vulnerability grading may identify risky plaques and therefore patients at a high risk of life threatening coronary events. In-fact, even when the current analysis was limited to plaques with lipid component and therefore potentially prone to rupture, the triple-feature grading OR between the two groups was very high (OR = 45,7). This approach promises to improve the characterization of plaque vulnerability obtained with other intracoronary imaging modalities. In the PROSPECT trial [6], patients harbouring lesions with three features of plaque vulnerability (MLA < 4 mm 2, plaque burden >70% and thin FCT according to virtual histology) had a MACE risk about 10 times higher than that observed in lesions without this composite end-point. However, the vast majority of MACE was related to plaque progression and not to ACS. FD-OCT has greater potential in bias the the

19 assessing plaque vulnerability than IVUS-virtual histology and seems more suited to address clinical endpoints of utmost importance, such as cardiac death and myocardial infarction. Imaging-based plaque characterization has the potential to identify patients at high risk for coronary events more accurately than other indirect clinical variables, such as systemic inflammatory markers [20], peripheral arterial disease or coronary multivessel disease, that have been applied in clinical studies on secondary prevention [22,23]. Undoubtedly, in addition to the still debated decision as to whether to treat the lesion with stent, such patients could benefit from aggressive and intensive medical treatment. Limitations The present study has some limitations. First, the number of patients enrolled in the study is small; however, this study was designed as a hypothesis-generating work and served as a pilot study for the large CLIMA registry (ClinicalTrials.gov Identifier: NCT ). Furthermore, the number of lesions we analysed in the present study was sufficient to reach our conclusions. Second, there is no comparison with pathology since it is an in vivo study. Our complex imaging modality however integrated three different imaging techniques (OCT, IVUS and NIRS), reciprocally matching and informing on precise plaques structures with the final output analysed using dedicated software. bias the the

20 Regarding OCT macrophage detection that remains challenging, we applied a well-validated OCTderived algorithm based on tissue property indexes [18]. Third, the matching of IVUS-NIRS and OCT images is complex. To ensure a precise match of images achieved with the different techniques, we used a validated approach that is based on the accurate identification of anatomical landmarks and lumen morphology at the sites of matching [16-17]. CONCLUSIONS Multimodality intravascular imaging demonstrates in vivo the co-presence of three pathologicallyvalidated features of vulnerability (MLA<4 mm 2, FCT <75 µm and superficial inflammatory cells) in the same culprit lesion in over 69% of ACS, a figure by far more common than in the control arm (OR over 40). The triple OCT grading is potentially capable of identifying vulnerable plaques with a much higher accuracy than that obtained applying single features of vulnerability. This finding sets the basis for a vulnerability grading system in vivo that first introduces the systematic search for superficially clustered macrophages. REFERENCES bias the the

21 1. Conroy RM, Pyörälä K, Fitzgerald AP, et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003;24: Goff DC Jr, Lloyd-Jones DM, Bennett G, et al ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63: Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation. 2003; 108: Narula J, Nakano M, Virmani R, et al. Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques. J Am Coll Cardiol. 2013;61: Motoyama S, Ito H, Sarai M, et al. Plaque Characterization by Coronary Computed Tomography Angiography and the Likelihood of Acute Coronary Events in Mid-Term Follow-Up. J Am Coll Cardiol. 2015;66: Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. N Engl J Med. 2011;364: Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J. 2012;33: bias the the

22 8. Xing L, Higuma T, Wang Z, et al. Significance of lipid-rich plaque detected by optical coherence tomography. A 4-Year Follow-Up Study. J Am Coll Cardiol 2017;69: Higuma T, Soeda T, Abe N, et al. A combined optical coherence tomography and intravascular ultrasound study on plaque rupture, plaque erosion, and calcified nodule in patients with ST-segment elevation myocardial infarction: incidence, morphologic characteristics, and outcomes after percutaneous coronary intervention. JACC Cardiovasc Interv. 2015: 17: Tanaka A, Imanishi T, Kitabata H, et al. Morphology of exertion-triggered plaque rupture in patients with acute coronary syndrome: an optical coherence tomography study. Circulation. 2008;23: Prati F, Regar E, Mintz GS, et al. Expert review document on methodology, terminology, and clinical applications of optical coherence tomography: physical principles, methodology of image acquisition, and clinical application for assessment of coronary arteries and atherosclerosis. Eur Heart J. 2010;31: Tearney GJ, Regar E, Akasaka T, et al. Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the bias the the

23 International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation. J Am Coll Cardiol. 2012;59: Kang SJ, Mintz GS, Pu J, et al. Combined IVUS and NIRS detection of fibroatheromas: histopathological validation in human coronary arteries. JACC Cardiovasc Imaging. 2015;2: Kato K, Yonetsu T, Kim SJ, et al. Nonculprit plaques in patients with acute coronary syndromes have more vulnerable features compared with those with non-acute coronary syndromes: a 3-vessel optical coherence tomography study. Circ Cardiovasc Imaging. 2012;5: 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: Paoletti G, Marco V, Romagnoli E, et al. Reproducibility of serial optical coherence tomography measurements for lumen area and plaque components in humans (The CLI- VAR [Centro per la Lotta Contro l'infarto-variability] II study). Int J Cardiovasc Imaging. 2016;32: bias the the

24 17. Souteyrand G, Arbustini E, Motreff P et al. Serial optical coherence tomography imaging of ACS-causing culprit plaques. EuroIntervention. 2015,11: Di Vito L, Agozzino M, Marco V, et al. Identification and quantification of macrophage presence in coronary atherosclerotic plaques by optical coherence tomography. Eur Heart J Cardiovasc Imaging. 2015;16: Falk E, Nakano M, Bentzon JF, Finn AV, Virmani R. Update on acute coronary syndromes: the pathologists view. Eur Heart J. 2013;34: Buffon A, Biasucci LM, Liuzzo G, D'Onofrio G, Crea F, Maseri A. Widespread coronary inflammation in unstable angina. N Engl J Med. 2002;347: Tearney GJ, Yabushita H, Houser SL, et al. Quantification of macrophage content in atherosclerotic plaques by optical coherence tomography. Circulation. 2003;107: Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372: Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012; 366: bias the the

25 FIGURE LEGENDS Figure 1. Study flow-chart. ACS: acute coronary syndromes, STEMI: ST elevation myocardial infarction, NSTEMI: non ST elevation myocardial infarction Figure 2. Odd Ratio of single and combined features of plaque vulnerability. Figure 1 supplementary. Examples of culprit ACS lesion with three features of vulnerability (panel A) and stable lesion without criteria of vulnerability (panel B). Panel A. Ulcerated plaque exhibiting the three main features of plaque vulnerability: superficial macrophages (dotted arrows) in the OCT panel and in the magnified OCT image (left), thin fibrous cap near the site of rupture (arrow) with lipid components (arrow-head) and significantly narrowed lumen (minimal lumen area bias the the

26 (MLA) 2,5 mm 2 ). Panel B: stable plaque. Thick fibrous cap of 180 µm in presence of lipid components at a site with a lumen area of 5,6 mm 2 (> 4 mm 2 ). Absence of macrophages. Figure 2 supplementary. Example of stable plaques with features of vulnerability but without the triple vulnerability grading. Panel A: plaque with superficial macrophages indicated by arrows in the OCT image (left) and in the magnified OCT image (mid). No lipids are detected by OCT and IVUS NIRS (right). The lumen is significantly narrowed with a 2,9 mm 2 minimal lumen area (MLA) Panel B: Plaque with lipid necrotic core (OCT and IVUS-NIRS images) and thin fibrous cap thickness (FCT) (dotted arrow in the OCT image). Panel C: fibrous plaque with calcium (arrow-head) causing a significant lumen area reduction (OCT and IVUS-NIRS image) Figure 3 supplementary. Upper left panel. ACS culprit lesion with fresh thrombus (arrow-head) and strong linear images bias the the (arrow), indicative of macrophage cluster. The application of the dedicated two-step algorithm for macrophage detection (upper right panel), using an OCT-derived

27 tissue property software, confirms presence of macrophages, showing a high value of normalized standard deviation. Lower left panel. Stable lesion with strong linear images (arrows), compatible with macrophage cluster. The application of the dedicated two-step algorithm for macrophage detection (upper right panel), excludes macrophages by showing a small value of normalized standard deviation. bias the the

28 Table 1. Procedural characteristics, OCT and IVUS-NIRS features in all lesions All lesions (99) Culprit group (21) Non-culprit group (78) p Location of lesion studied Left main (%) 6 (6.1) 2 (9.5) 4 (5.1) Left anterior descending artery (%) 54 (54.5) 9 (42.9) 45 (57.7) Left circumflex artery (%) 19 (19.2) 6 (28.6) 13 (16.7) Right coronary artery (%) 20 (20.2) 4 (19.0) 16 (20.5) IVUS-NIRS features LCBI reg* 248.4± ± ± Lipid Arc ( )* 81.6± ± ± Lipid Arc >90 (%) 37 (37.4) 12 (57.1) 25 (32.1) Plaque Burden (%)* 61.5± ± ± Plaque Burden >70% 29 (29.3) 7 (33.3) 22 (28.2) Angiography features Minimum Lumen Diameter (mm)* 0.99± ± ± Reference Vessel Diameter (mm)* 2.97± ± ± Stenosis percentage (%)* 66.5± ± ± OCT features bias the the

29 Minimum Lumen Area (mm 2 )* 3.4± ± ±2.1 <0.001 MLA <4.0 (mm 2 ) 72 (72.7) 21 (100.0) 51 (65.4) Fibrous cap thickness (µm) 165.2± ± ±114.1 <0.001 FCT <75 µm (%) 21 (21.2) 14 (66.7) 7 (9.0) <0.001 Macrophages (%) 60 (60.6) 16 (76.2) 44 (56.4) Distance from lumen area (µm)* 102.9± ± ±103.6 <0.001 Superficial (distance <80 µm, %) 34 (34.3) 14 (66.7) 20 (25.6) <0.001 Cholesterol crystal (%) 13 (13.1) 1 (4.8) 12 (15.4) Vasa vasorum (%) 13 (13.1) 3 (14.3) 10 (12.8) Thrombus (%) 21 (21.2) 21 (100.0) 0 (0.0) <0.001 Calcified nodules (%) 5 (5.1) 2 (9.5) 3 (3.8) Composite of MLA<4.0 mm 2, FCT <75 µm and superficial macrophages <80 µm bias the the 16 (16.2) 13 (61.9) 3 (3.8) <0.001 IVUS-NIRS = Intra-Vascular Ultrasound-Near Infrared Spectroscopy; LCBI = Lipid Core Burden Index; OCT = Optical Coherence Tomography; MLA = Minimum Lumen Area; FCT = Fibrous Cap Thickness; * Expressed as mean and standard deviation.

30 Table 2. Predictive value of NIRS-OCT criteria for all plaques Single Grading LBCI >400 OR 2.52 ( ) IVUS-NIRS Lipid Arc >90 OR 2.83 ( ) IVUS-NIRS Plaque Burden >70% OR 1.98 ( ) OCT MLA <4.0 (mm 2 )* OR ( ) FCT <75 µm (%) OR ( ) <0.001 OCT Macrophages (%) OR 2.47 ( ) OCT Superficial Macrophages <80 µm (%) OR 5.80 ( ) Composite grading MLA<4.0 mm2 and FCT <75 µm OR ( ) <0.001 MLA<4.0 mm2 and superficial macrophages <80 µm OR 7.43 ( ) <0.001 FCT <75 µm and superficial macrophages <80 µm OR ( ) <0.001 MLA<4.0 mm2, FCT <75 µm and superficial macrophages <80 µm bias the the OR ( ) <0.001 IVUS-NIRS = Intra-Vascular Ultrasound-Near Infrared Spectroscopy; OCT = Optical Coherence Tomography; MLA = Minimum Lumen Area; FCT = Fibrous Cap Thickness; * Expressed as mean and standard deviation.

31 Highlights The presence of three OCT features of vulnerability in the same lesion predicts acute events Presence of superficial macrophages is more common in plaques with acute local thrombosis OCT lesion characterization can help identifying patients at increased risk of adverse event bias the the

32 Figure 1

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35 Figure 4

36 Figure 5

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