In vivo coronary lesion differentiation with computed tomography angiography and intravascular ultrasound as compared to optical coherence tomography

Accepted Manuscript In vivo coronary lesion differentiation with computed tomography angiography and intravascular ultrasound as compared to optical coherence tomography Wouter G. Wieringa, Chris P.H. Lexis, Erik Lipsic, Hindrik W. van der Werf, Johannes G.M. Burgerhof, Vincent E. Hagens, G. Louis Bartels, Alexander Broersen, Remco A. Schurer, Eng-Shiong Tan, Pim van der Harst, Ad F.M. van den Heuvel, Tineke P. Willems, Gabija Pundziute PII:

S1934-5925(17)30020-5

DOI:

10.1016/j.jcct.2017.01.004

Reference:

JCCT 952

To appear in:

Journal of Cardiovascular Computed Tomograph

Received Date: 24 November 2014 Revised Date:

20 December 2016

Accepted Date: 14 January 2017

Please cite this article as: Wieringa WG, Lexis CPH, Lipsic E, van der Werf HW, Burgerhof JGM, Hagens VE, Bartels GL, Broersen A, Schurer RA, Tan E-S, van der Harst P, van den Heuvel AFM, Willems TP, Pundziute G, In vivo coronary lesion differentiation with computed tomography angiography and intravascular ultrasound as compared to optical coherence tomography, Journal of Cardiovascular Computed Tomograph (2017), doi: 10.1016/j.jcct.2017.01.004. 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.

ACCEPTED MANUSCRIPT

In Vivo Coronary Lesion Differentiation with Computed Tomography Angiography and Intravascular Ultrasound as Compared to Optical

RI PT

Coherence Tomography

Wouter G Wieringa MD1, Chris PH Lexis MD1, Erik Lipsic MD PhD1, Hindrik W

van der Werf MD1, Johannes GM Burgerhof MSc4, Vincent E Hagens MD PhD5,

SC

G Louis Bartels MD PhD6, Alexander Broersen PhD3, Remco A Schurer MD1,

M AN U

Eng-Shiong Tan MD PhD1, Pim van der Harst MD PhD1, Ad FM van den Heuvel MD PhD1, Tineke P Willems MD PhD2, Gabija Pundziute MD PhD1 1

University of Groningen, University Medical Center Groningen, Thorax Center, Department of

Cardiology, Groningen, The Netherlands; 2

University of Groningen, University Medical Center Groningen, Department of Radiology,

Groningen, The Netherlands; 3

University of Leiden, Leiden University Medical Center, Department of Radiology, Division of

TE D

Image Processing, Leiden, The Netherlands; 4

University of Groningen, University Medical Center Groningen, Department of Epidemiology,

Groningen, The Netherlands; 5

Ommelander Group, Delfzicht Hospital, Department of Cardiology, The Netherlands

6

EP

Martini Hospital, Department of Cardiology, Groningen, The Netherlands

AC C

Address for correspondence: G Pundziute; Thorax Center, Department of Cardiology University Medical Center Groningen Hanzeplein 1 PO Box 30001 9700 RP Groningen, The Netherlands Tel: +31 50 3612355 | Fax: +31 50 3612355 | Email: [email protected]

Manuscript type: Original research Word count: 5143 -1-

ACCEPTED MANUSCRIPT

Abstract Background In vitro studies have shown the feasibility of coronary lesion grading

RI PT

with computed tomography angiography (CTA), intravascular ultrasound (IVUS) and optical coherence tomography (OCT) as compared to histology, whereas OCT had the highest discriminatory capacity.

Objective We investigated the ability of CTA and IVUS to differentiate between

SC

early and advanced coronary lesions in vivo, OCT serving as standard of reference.

M AN U

Methods Multimodality imaging was prospectively performed in 30 NSTEMI patients. Plaque characteristics were assessed in 1083 cross-sections of 30 culprit lesions, co-registered among modalities. Absence of plaque, fibrous and fibrocalcific plaque on OCT were defined as early plaque, whereas lipid rich-

TE D

plaque on OCT was defined as advanced plaque. Odds ratios adjusted for clustering were calculated to assess associations between plaque types on CTA and IVUS with early or advanced plaque.

EP

Results Normal findings on CTA as well as on IVUS were associated with early plaque. Non-calcified, calcified plaques and the napkin ring sign on CTA were

AC C

associated with advanced plaque. On IVUS, fatty and calcified plaques were associated with advanced plaque. Conclusions In vivo coronary plaque characteristics on CTA and IVUS are associated with plaque characteristics on OCT. Of note, normal findings on CTA and IVUS relate to early lesions on OCT. Nevertheless, multiple plaque features

-2-

ACCEPTED MANUSCRIPT

on CTA and IVUS are related to advanced plaques on OCT, which may make it

RI PT

difficult to use qualitative plaque assessment in clinical practice.

Key words: computed tomography, intravascular ultrasound, optical coherence

Abbreviations and acronyms CAD = coronary artery disease

M AN U

SC

tomography, coronary atherosclerosis.

TE D

CTA = computed tomography angiography HU = Houndsfield units

ICA = invasive coronary angiography

EP

IVUS = intravascular ultrasound

NSTEMI = non-ST-elevation myocardial infarction

AC C

OCT = optical coherence tomography OR = odds ratio

TCFA = thin cap fibro-atheroma

-3-

ACCEPTED MANUSCRIPT

1. Introduction Rupture of an atherosclerotic plaque with superimposed luminal coronary artery

RI PT

thrombosis is the most common cause of acute coronary events. On histologic examination, coronary artery plaques that are prone to rupture typically contain a large necrotic lipid-rich core and a thin overlying fibrous cap and are often

referred to as vulnerable plaques 1, 2. Early detection of vulnerable plaques could

SC

potentially prevent coronary events. Computed tomography angiography (CTA) of the coronary arteries is a clinically established tool enabling non-invasive

M AN U

diagnosis of coronary artery disease (CAD). Besides stenosis assessment, it is possible to assess composition of atherosclerotic plaques with CTA and to a certain extent classify plaques 3. Although the presence of non-calcified plaque component on CTA was associated with the development of coronary events 4,

TE D

the capability to discriminate between components of non-calcified plaque is still not well established 5, 6.

A multi-modality imaging strategy may enhance our understanding of coronary

EP

atherosclerotic lesions that are related to coronary events. Invasive coronary plaque characterization may be performed using intravascular ultrasound (IVUS)

AC C

and optical coherence tomography (OCT)7. Whereas, IVUS is regarded as reference method for coronary plaque dimensions, OCT has shown a high diagnostic accuracy in characterization of plaques, however its penetration depth is limited 8, 9. The feasibility of coronary lesion grading with CTA, IVUS and OCT as compared to histology was elegantly shown in an in vitro setting 10, 11. OCT yielded the -4-

ACCEPTED MANUSCRIPT

highest discriminatory capacity as compared to histology 10. Accordingly, in the study we investigated the ability of CTA and IVUS to differentiate between

RI PT

atherosclerotic plaque characteristics in vivo, with OCT serving as a standard of reference.

2. Materials and methods

SC

Thirty patients presenting with non-ST-elevation myocardial infarction (NSTEMI) were prospectively included in our study. Inclusion criteria for the study were

M AN U

patients with NSTEMI - chest pain suggestive for myocardial ischemia with typical electrocardiogram changes and a rise of (high sensitivity) troponin T - with a clinical indication for invasive coronary angiography (ICA) followed by reperfusion of the ischemia-related target lesion. The culprit lesion was identified

TE D

using a combination of electrocardiogram, ICA and, if available, wall motion abnormalities seen on cardiac ultrasound. Only native coronary artery lesions were included. Exclusion criteria were: persistent ST-segment elevation (>1mm

EP

in 2 or more leads), the need for emergency ICA with subsequent PCI or coronary artery bypass grafting, presence of cardiogenic shock, contraindication

AC C

to CTA (estimated glomerular filtration rate <50 ml/min, known allergy to iodine contrast agents, no sinus rhythm, inability to lay supine or sustain a breath-hold for 15 seconds) and no informed consent. CTA, IVUS and OCT were performed within 24 hours and all imaging modalities were performed before coronary intervention. The study was approved by the local ethics committee and was

-5-

ACCEPTED MANUSCRIPT

carried out according to the Declaration of Helsinki. Written informed consent

2.1 Computed tomography angiography 2.1.1 Image acquisition

RI PT

was obtained from each participant.

CTA was performed using a 64-slice dual-source computed tomography scanner

SC

(Somatom Definition, Siemens Healthcare, Germany), with the following scan

parameters: 64x2x0.6mm collimation, 330ms gantry rotation time, 83ms temporal

M AN U

resolution, tube voltage 100-120mV, and maximal tube current of 560mAs. 2.1.2 Image analysis

CTA images were evaluated on a remote workstation with dedicated software (QAngio CT, Medis Medical Imaging Systems, the Netherlands) 12 in consensus

TE D

by two experienced observers blinded to other imaging modalities. A predefined window and level setting (window 700HU, level 200HU) was used for analysis of lumen and plaque, and manipulated for optimal analysis if deemed necessary.

EP

Analysis of presence and composition of atherosclerosis were performed on a per lesion and on a per cross-sectional basis. In addition, in all other existing

AC C

coronary segments the presence, composition of plaque and the degree of stenosis were analyzed. Coronary segments were differentiated into seventeen segments, according to a modified American Heart Association classification 13. Plaques with a luminal coronary artery narrowing ≥50% were classified as obstructive. The composition of plaque was classified to one of three types: 1. non-calcified plaque (plaques with lower density compared to contrast-enhanced -6-

ACCEPTED MANUSCRIPT

lumen), 2. calcified plaque (plaques with only high density structures visible compared to contrast-enhanced lumen), or 3. mixed plaque (non-calcified and

RI PT

calcified constituents in single plaque). The presence of thrombus was assessed on per segment level, which was defined as a homogenous non-calcified structure with irregular borders with a density of <55HU 14.

On cross-sections with non-calcified plaque component (non-calcified and mixed

SC

plaques) presence of napkin-ring sign was scored as a plaque core with low CTA attenuation surrounded by a rim-like area of higher attenuation 15. Non-calcified

M AN U

and mixed plaques were additionally classified according to their attenuation as low-attenuation (<30HU) and higher attenuation (≥30HU) plaques 16. Plaque attenuation was measured at three points within the non-calcified plaque; the

TE D

average of three measurements was used.

2.2 Intravascular ultrasound 2.2.1 Image acquisition

EP

The IVUS catheter (40MHz Atlantis SR pro catheter, Boston Scientific, USA) was advanced over the guidewire. Acquisition was performed using the iLab

AC C

ultrasound imaging system (Boston Scientific, USA). IVUS images were obtained during automatic pullback at a rate of 0.5mm/s. 2.2.2 Image analysis

Off-line IVUS and OCT cross-section analyses were performed using dedicated software (QIvus 2.1, Medis medical imaging systems, the Netherlands) in consensus by two observers blinded to all other image modalities of the same -7-

ACCEPTED MANUSCRIPT

patient. Assessment of IVUS cross-sections was performed in accordance with the working group on intracoronary imaging of the European Society of

RI PT

Cardiology using the following criteria 8: normal vessel wall, <0.3mm of intimamedia thickness; vessel wall containing plaque, ≥0.3 mm of intima-media

thickness; fibrous plaque, >2 quadrants constituted by tissue with echoreflectivity higher than that of the adventitia; fatty plaque, >2 quadrants constituted by tissue

SC

with echoreflectivity lower than that of the adventitia; fibrocalcific plaque, <2

arc.

M AN U

quadrants of total calcified arc; and calcified plaque, >2 quadrants of total calcific

2.3 Optical coherence tomography 2.3.1 Image acquisition

TE D

OCT acquisition was performed using the C7 imaging system (St. Jude/LightLab Imaging Inc, USA). The OCT catheter (DragonFly catheter, St. Jude Medical/LightLab Imaging Inc, USA) was advanced over the guidewire and

EP

placed distal to the lesion. OCT images were obtained during the intracoronary injection of 13-20ml of contrast medium (Xenetix 300, Guerbet, France) at a rate

AC C

of 3-4ml/s and an automatic pullback at a rate of 20mm/s. 2.3.1 Image analysis

On OCT cross-sections morphological characterization of plaques was performed as follows 9: normal vessel wall; fibrous plaque, homogenous high-backscattering areas; fibrocalcific plaque, fibrous plaques with calcific areas (well-delineated, low back-scattering heterogenous regions); lipid-rich plaque, signal poor regions -8-

ACCEPTED MANUSCRIPT

with diffuse borders in >2 quadrants. Thin cap fibro-atheroma (TCFA) was defined as a lipid-rich plaque with an overlying fibrous cap with a thickness of

RI PT

≤65µm 17. When a cross-section showed various plaque types, the most advanced plaque type was assigned in the following order: lipid-rich

plaque>fibrocalcific plaque>fibrous plaque. For comparisons we categorized

plaques in early and advanced plaques. Based on associations found in the ex

SC

vivo study by Maurovich-Horvat et al. absence of plaque, fibrous and fibrocalcific plaques were defined as early plaques and lipid-rich plaques were defined as

M AN U

advanced plaques 10. Plaque rupture was identified as the presence of fibrouscap discontinuity with a cavity formation in the plaque 18. Presence of thrombus was visually assessed. Intracoronary thrombus was defined as a mass protruding

TE D

the coronary vessel lumen discontinuous from the vessel wall 9.

2.4 Image co-registration

Anatomic landmarks, such as side-branches and/or calcifications were used to

EP

align CTA, IVUS and OCT images and co-registered cross-sections. Multiplanar CTA reconstructions were created perpendicular to the vessel centerline. Initially,

AC C

a visual co-registration was performed to align CTA, IVUS and OCT longitudinal segments. Subsequently, dedicated software (Matcher, Medis Medical Imaging Systems, the Netherlands) was used to confirm the performed visual coregistration. Anatomic landmarks were used to match the rotational direction of the cross-sections of CTA, IVUS and OCT.

-9-

ACCEPTED MANUSCRIPT

2.5 Statistical analysis Normally distributed continuous variables are presented as mean±SD. Continuous variables with skewed distribution are presented as medians with 25th

RI PT

and 75th percentile. Categorical variables are presented as numbers and

percentages. Group differences were tested using ANOVA test, Pearson χ2, or Fisher’s exact test where appropriate.

SC

Crude associations of each category of CTA and IVUS with early or advanced

plaque defined by OCT were assessed by calculating odds ratios (OR) for each

M AN U

category with the odds of normal plaque serving as reference. An OR>1.0 indicated an increased probability of a lesion being advanced, and an OR<1.0 indicated an increased probability of a lesion being early. Significance of these crude associations was tested using the Fisher’s exact test. Additionally the

TE D

associations were recalculated accounting for clustering effect within lesions, using multilevel mixed effect modeling. A mixed effects logistic regression for each modality was fitted with the category normal plaque serving as the

EP

reference category. Because of multiple testing, P-values were adjusted using Bonferroni correction.

AC C

The interobserver agreement for plaque classification was assessed for each modality by using Cohen κ statistics interpreted as follows: A κ value of > 0.80 corresponded to excellent agreement a κ value between 0.61 and 0.80 corresponded to good interobserver agreement and a κ value between 0.41 and 0.60 corresponded tot moderate agreement.

- 10 -

ACCEPTED MANUSCRIPT

Statistical significance was defined as P-value of <0.05. Statistical analyses were

RI PT

performed using STATA version 11 (College Station, USA).

3. Results 3.1 Study population

Patients were included during a period of two years, from January 2012 until May

SC

2013. During that period 144 patients were eligible to participate in the study. Of those patients, 41 (28.5%) patients gave informed consent and 103 (71.5%) were

M AN U

not invited to participate or did not provide consent due to different reasons. Most of eligible patients were not invited to participate in the study due to the organizational problems at the coronary care unit of one participating center at the time of the study. Out of 41 patients, who agreed to participate in the study,

TE D

due to logistical problems a total of 2 who gave their consent could eventually not be included in the study. In 9 patients OCT could not be performed due to heavy calcifications or tight coronary artery lesions or coronary artery occlusion, which

EP

became evident on invasive angiogram. Consequently, 30 patients with NSTEMI were included in the study and multi-modality imaging was performed in 30 culprit

AC C

lesions, resulting in a total of 1083 cross-sections available for analysis. The mean number of available cross-sections was 36 per patient. Baseline characteristics of the population are presented in Table 1.

3.2 Computed tomography angiography

- 11 -

ACCEPTED MANUSCRIPT

On lesion level, the majority of the culprit coronary plaques (17; 56.7%) were classified as mixed plaques, whereas 5 (16.6%) were classified as non-calcified

RI PT

plaques and 8 (26.7%) were classified as calcified plaques. Thrombus was scored in 9 (30.0%) culprit segments (Table 2).

On cross-sectional level, of the 1083 CTA cross-sections, 257 (23.7%) were

classified as normal, 360 (33.2%) as showing non-calcified plaque, 178 (16.4%)

SC

as showing mixed plaque, and 288 (26.7%) as showing calcified plaque. Twenty-

ring sing.

3.4 Intravascular ultrasound

M AN U

eight (5.2%) of all 538 non-calcified and mixed cross-sections exhibited a napkin-

On lesion level, characteristics visualized by IVUS where as follows: thrombus

(43.3%) plaques.

TE D

was detected in 8 (26.7%) culprit segments, and rupture was detected in 13

On cross-sectional level, of the 1083 IVUS cross-sections, 45 (4.2%) were

EP

classified as normal, 380 (35.1%) as fibrous plaques, 369 (34.0%) as fibrocalcific plaques, 173 (16.0%) as calcified plaques, and 116 (10.7%) as fatty plaques.

AC C

Thrombus was detected in 21 (1.9%) cross-sections.

3.5 Optical coherence tomography On lesion level, thrombus was detected in 20 (66.7%), plaque rupture in 25 (83.3%), and TCFA in 13 (43.3%) of the culprit lesions.

- 12 -

ACCEPTED MANUSCRIPT

On cross-sectional level, of the 1083 OCT cross-sections, 35 (3.3%) were classified as normal, 296 (27.3%) as fibrous plaques, 467 (43.1%) as fibrocalcific

(9.0%) frames. TCFA was present in 24 (2.2 %) frames.

RI PT

plaques and 285 (26.3%) as lipid-rich plaques. Thrombus was present in 97

3.6 Comparison between computed tomography angiography versus

SC

intravascular ultraround.

On lesion level, all 30 coronary plaques that were visible on IVUS were also

M AN U

detected on CTA.

On cross-sectional level, we used the cutoff value of 0.5 mm to compare the ability of CT to detect plaque. Out of 1083 frames analyzed on IVUS, 53 frames had the mean plaque thickness of <0.5 mm, whereas 1030 plaques were ≥0.5

TE D

mm. In 795 of 1030 (77.2%) frames with a mean plaque thickness of ≥0.5 mm the plaques were also detected on CTA, whereas the minimal plaque of <0.5 mm on IVUS was not detectable on CTA in 35 of 53 (66.0%) of frames.

EP

We also repeated this analysis using a plaque burden of < or ≥40% on IVUS as a standard of reference (which is considered to be a relevant amount of coronary

AC C

plaque). Out of 1083 frames analyzed on IVUS, 878 frames had plaque burden of ≥40%, whereas 205 plaques had a plaque burden of <40%. In 742/878 (84.5%) of frames on IVUS the plaque was detected on CTA, whereas 134/205 (65.3%) of plaques with the area of <40% were not detected on CTA, resulting in a sensitivity of CTA of 84.5% to detect plaque with a burden of ≥40% on IVUS.

- 13 -

ACCEPTED MANUSCRIPT

3.7 Comparison between computed tomography angiography versus optical coherence tomography

RI PT

On per lesion basis, culprit lesions were grouped based on the presence of thrombus on OCT (Table 2). Correlation was observed between the low

attenuation value on CTA and the presence of thrombus on OCT. Nevertheless, no correlation was observed between the plaque type on CTA and the presence

SC

of thrombus. The sensitivity for CTA to detect thrombus was 45% (9/20) and the specificity was 100% (10/10).

M AN U

On per cross-section basis, thrombus was visible in only 21% of CTA frames with thrombus on OCT (Table 2). The same limited association was observed between the presence of thrombus on OCT and the napkin-ring sign and low attenuation plaque.

TE D

Normal findings on CTA were associated with early plaque on OCT (Tables 3 and 4). Non-calcified and calcified plaques were associated with advanced plaque on OCT. Napkin-ring sign was significantly associated with advanced

EP

plaque on OCT (OR:4.66, p<0.001).

AC C

3.8 Comparison between intravascular ultrasound versus optical coherence tomography

On lesion level, a very limited correlation between the presence of thrombus on OCT and IVUS was observed (Table 2). The sensitivity and specificity of thrombus detection were 30% (6/20) and 80% (8/10), respectively.

- 14 -

ACCEPTED MANUSCRIPT

On cross-sectional level, the correlation between the presence of thrombus on OCT and the findings on IVUS was even lower than on lesion level (Table 2).

RI PT

Normal findings on IVUS were associated with early plaque on OCT (Tables 3 and 4). On the contrary, calcified plaque was associated with advanced plaque

on OCT, whereas fatty plaque on IVUS was strongly associated with advanced plaque on OCT.

SC

An example of findings on all three imaging modalities are presented in Figures 1

3.9 Interobserver variability

M AN U

and 2.

The interobserver variability was assessed in 10 patients. For CT angiography for the normal vessel and the three categories of plaques the agreement was

TE D

excellent (Cohen κ = 0.96), with the majority of the disagreements occurring between the classification as calcified or mixed plaque. The overall agreement for the normal vessel and four plaque categories of IVUS was excellent (Cohen κ =

EP

0.87), with most differences in grading of fibrous versus lipid, and calcified versus fibrocalcific plaque. The interobserver variability of the readers for the

AC C

normalvessel en three OCT plaque characteristics was excellent (Cohen κ = 0.93), with disagreement occurring mainly between fibrous and lipid plaques.

4. Discussion

In the present in vivo study in patients with NSTEMI, describing a systematic assessment of coronary lesions, using CTA and IVUS compared to OCT as a - 15 -

ACCEPTED MANUSCRIPT

standard of reference, the findings may be summarized as follows: [1] Normal findings on CTA and IVUS are associated with early plaque as defined by OCT;

RI PT

[2] Non-calcified plaque, napkin-ring sign and calcified plaque on CTA as well as fatty and calcified plaque on IVUS are significantly associated with advanced plaque as defined by OCT.

In accordance with ex vivo studies, the absence of plaque on CTA was correlated

SC

to early plaque on OCT 10, 11. Indeed, Maurovich-Horvath et al. have observed in an experimental model that normal findings by CTA were associated with early

M AN U

atherosclerotic plaque on histological examination (OR: 0.02; p<0.001) 10. The finding is also in line with prognostic studies which have shown that the absence of CAD on CTA resulted in no coronary events during follow-up 19. This finding further supports the application of coronary CTA for exclusion of CAD. Moreover,

TE D

correlation between certain coronary plaque characteristics on CTA and advanced lesions on OCT has been observed. A significant correlation between non-calcified plaque on CTA and advanced plaque on OCT has been found in

EP

our dataset, which is contrary to the findings in the previous ex vivo study where correlation between advanced lesions on histology and mixed plaque on CTA

AC C

was observed 10. From a clinical point of view both types of plaques (noncalcified and mixed) were related to coronary events on follow-up 4, 20-23. Another interesting observation is the correlation between the napkin-ring sign on CTA and advanced coronary plaque. Previous studies have shown the relation between the napkin-ring sign and high-risk coronary plaques 11, 24-26. In a study with seven donor hearts the specificity of napkin-ring sign to identify - 16 -

ACCEPTED MANUSCRIPT

histopathologically advanced lesions and TCFA was as high as 99% 11. Moreover, another study with 1469 patients who underwent CTA for the evaluation of CAD demonstrated that the presence of napkin-ring sign within a

RI PT

coronary plaque is associated with future cardiac events 23. Nevertheless, we have also observed a correlation between advanced lesions on OCT and

calcified plaque on CTA. A trend towards this correlation has been reported in a

SC

study by Maurovich-Horvat et al.10.

Similar correlations as with CTA were observed also on IVUS. Indeed, normal

M AN U

findings on IVUS were related to early lesions on OCT, whereas a strong correlation between the fatty plaque on IVUS and advanced plaque on OCT was observed. Also, similar to the findings on CTA calcified plaque on IVUS was related to advanced lesions. The findings are somewhat discrepant from the

TE D

findings in a previous ex vivo study 10, which could be related to different classification scheme applied in our study and a small sample size. In the present study we also assessed the ability of CTA and IVUS with inferior

EP

spatial resolution as compared to OCT to characterize non-calcified plaque components, including the assessment of thrombus. Thrombus was present in

AC C

66.7% of culprit lesions evaluated with OCT, which corresponds well to the prevalence of thrombus in previous studies on culprit lesions of NSTEMI patients using OCT (65 – 68%) 27, 28. Nevertheless, thrombus could only be identified in 30% of culprit lesions on IVUS. Our results correspond with the findings by Kubo et al., who reported the diagnostic accuracy for detection of thrombus by IVUS to be as low as 33% as compared to OCT and coronary angioscopy 18. Regarding - 17 -

ACCEPTED MANUSCRIPT

CTA, there are only a few reports available on the detection of coronary thrombus 14. As expected, the accuracy of thrombus detection on CTA in our

RI PT

study was as low as 45%. Moreover, no other plaque features were clearly associated with intracoronary thrombus on IVUS and CTA either on segmental or cross-section level (Table 2), which further emphasizes the limitation of grayscale IVUS and CTA to characterize non-calcified tissue. Accordingly, the

SC

presence of thrombus on gray-scale IVUS and CTA should be interpreted with caution.

M AN U

Our results should be interpreted in the context of several limitations. First, an important limitation of this study is the lack of histopathological data, however this study was designed as an in vivo study. Second, as the used modalities are different from the technical point of view, the plaque classification schemes were

to perform.

EP

5. Conclusion

TE D

also different. Therefore direct comparison of plaque characteristics was difficult

In conclusion, in vivo coronary plaque characteristics on CTA and IVUS are

AC C

associated with plaque characteristics on OCT. Of note, normal findings on CTA and IVUS relate to early lesions on OCT. Nevertheless, multiple plaque features on CTA and IVUS are associated with advanced plaques on OCT which may make it difficult to use qualitative plaque assessment to recognize advanced coronary plaques in clinical practice. Future studies in bigger samples are necessary to confirm the findings. - 18 -

ACCEPTED MANUSCRIPT

6. REFERENCES

RI PT

1. Kolodgie FD, Burke AP, Farb A, Gold HK, Yuan J, Narula J, Finn AV, Virmani R: The thin-cap fibroatheroma: a type of vulnerable plaque: the major precursor lesion to acute coronary syndromes. Curr Opin Cardiol 2001, 16(5):285-292.

SC

2. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM: Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000, 20(5):1262-1275.

M AN U

3. Voros S, Rinehart S, Qian Z, Joshi P, Vazquez G, Fischer C, Belur P, Hulten E, Villines TC: Coronary atherosclerosis imaging by coronary CT angiography: current status, correlation with intravascular interrogation and meta-analysis. JACC Cardiovasc Imaging 2011, 4(5):537-548.

TE D

4. van Werkhoven JM, Schuijf JD, Gaemperli O, Jukema JW, Kroft LJ, Boersma E, Pazhenkottil A, Valenta I, Pundziute G, de Roos A, van der Wall EE, Kaufmann PA, Bax JJ: Incremental prognostic value of multi-slice computed tomography coronary angiography over coronary artery calcium scoring in patients with suspected coronary artery disease. Eur Heart J 2009, 30(21):2622-2629.

EP

5. Marwan M, Taher MA, El Meniawy K, Awadallah H, Pflederer T, Schunback A, Ropers D, Daniel WG, Achenbach S: In vivo CT detection of lipid-rich coronary artery atherosclerotic plaques using quantitative histogram analysis: A head to head comparison with IVUS. Atherosclerosis 2011, 215:110–115.

AC C

6. Voros S, Rinehart S, Qian Z, Vazquez G, Anderson H, Murrieta L, Wilmer C, Carlson H, Taylor K, Ballard W, Karmpaliotis D, Kalynych A, Brown III C: Prospective Validation of Standardized, 3-Dimensional, Quantitative Coronary Computed Tomographic Plaque Measurements Using Radiofrequency Backscatter Intravascular Ultrasound as Reference Standard in Intermediate Coronary Arterial Lesions : Results From the ATLANTA (Assessment of Tissue Characteristics, Lesion Morphology, and Hemodynamics by Angiography With Fractional Flow Reserve, Intravascular Ultrasound and Virtual Histology, and Noninvasive Computed Tomography in Atherosclerotic Plaques) I Study. JACC Cardiovasc Interv. 2011, 4(2):198-208. - 19 -

ACCEPTED MANUSCRIPT

RI PT

7. Kawasaki M, Bouma BE, Bressner J, Houser SL, Nadkarni SK, MacNeill BD, Jang IK, Fujiwara H, Tearney GJ: Diagnostic accuracy of optical coherence tomography and integrated backscatter intravascular ultrasound images for tissue characterization of human coronary plaques. J Am Coll Cardiol 2006, 48(1):81-88.

SC

8. Di Mario C, Gorge G, Peters R, Kearney P, Pinto F, Hausmann D, von Birgelen C, Colombo A, Mudra H, Roelandt J, Erbel R: Clinical application and image interpretation in intracoronary ultrasound. Study Group on Intracoronary Imaging of the Working Group of Coronary Circulation and of the Subgroup on Intravascular Ultrasound of the Working Group of Echocardiography of the European Society of Cardiology. Eur Heart J 1998, 19(2):207-229.

EP

TE D

M AN U

9. Tearney GJ, Regar E, Akasaka T, Adriaenssens T, Barlis P, Bezerra HG, Bouma B, Bruining N, Cho JM, Chowdhary S, Costa MA, de Silva R, Dijkstra J, Di Mario C, Dudek D, Falk E, Feldman MD, Fitzgerald P, Garcia-Garcia HM, Gonzalo N, Granada JF, Guagliumi G, Holm NR, Honda Y, Ikeno F, Kawasaki M, Kochman J, Koltowski L, Kubo T, Kume T, Kyono H, Lam CC, Lamouche G, Lee DP, Leon MB, Maehara A, Manfrini O, Mintz GS, Mizuno K, Morel MA, Nadkarni S, Okura H, Otake H, Pietrasik A, Prati F, Raber L, Radu MD, Rieber J, Riga M, Rollins A, Rosenberg M, Sirbu V, Serruys PW, Shimada K, Shinke T, Shite J, Siegel E, Sonoda S, Suter M, Takarada S, Tanaka A, Terashima M, Thim T, Uemura S, Ughi GJ, van Beusekom HM, van der Steen AF, van Es GA, van Soest G, Virmani R, Waxman S, Weissman NJ, Weisz G, International Working Group for Intravascular Optical Coherence Tomography (IWG-IVOCT): Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation. J Am Coll Cardiol 2012, 59(12):1058-1072.

AC C

10. Maurovich-Horvat P, Schlett CL, Alkadhi H, Nakano M, Stolzmann P, Vorpahl M, Scheffel H, Tanaka A, Warger WC,2nd, Maehara A, Ma S, Kriegel MF, Kaple RK, Seifarth H, Bamberg F, Mintz GS, Tearney GJ, Virmani R, Hoffmann U: Differentiation of early from advanced coronary atherosclerotic lesions: systematic comparison of CT, intravascular US, and optical frequency domain imaging with histopathologic examination in ex vivo human hearts. Radiology 2012, 265(2):393-401. 11. Maurovich-Horvat P, Schlett CL, Alkadhi H, Nakano M, Otsuka F, Stolzmann P, Scheffel H, Ferencik M, Kriegel MF, Seifarth H, Virmani R, Hoffmann U: The napkin-ring sign indicates advanced atherosclerotic lesions in coronary CT angiography. JACC Cardiovasc Imaging 2012, 5(12):1243-1252. - 20 -

ACCEPTED MANUSCRIPT

RI PT

12. Boogers MJ, Schuijf JD, Kitslaar PH, van Werkhoven JM, de Graaf FR, Boersma E, van Velzen JE, Dijkstra J, Adame IM, Kroft LJ, de Roos A, Schreur JH, Heijenbrok MW, Jukema JW, Reiber JH, Bax JJ: Automated quantification of stenosis severity on 64-slice CT: a comparison with quantitative coronary angiography. JACC Cardiovasc Imaging 2010, 3(7):699-709. 13. Austen WG, Edwards JE, Frye RL, Gensini GG, Gott VL, Griffith LS, McGoon DC, Murphy ML, Roe BB: A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation 1975, 51(4 Suppl):5-40.

SC

14. Achenbach S, Marwan M: Intracoronary thrombus. J Cardiovasc Comput Tomogr 2009, 3(5):344-345.

M AN U

15. Maurovich-Horvat P, Hoffmann U, Vorpahl M, Nakano M, Virmani R, Alkadhi H: The napkin-ring sign: CT signature of high-risk coronary plaques? JACC Cardiovasc Imaging 2010, 3(4):440-444. 16. Motoyama S, Kondo T, Anno H, Sugiura A, Ito Y, Mori K, Ishii J, Sato T, Inoue K, Sarai M, Hishida H, Narula J: Atherosclerotic plaque characterization by 0.5-mm-slice multislice computed tomographic imaging. Circ J 2007, 71(3):363-366.

TE D

17. Kume T, Akasaka T, Kawamoto T, Okura H, Watanabe N, Toyota E, Neishi Y, Sukmawan R, Sadahira Y, Yoshida K: Measurement of the thickness of the fibrous cap by optical coherence tomography. Am Heart J 2006, 152(4):755.e1-755.e4.

AC C

EP

18. Kubo T, Imanishi T, Takarada S, Kuroi A, Ueno S, Yamano T, Tanimoto T, Matsuo Y, Masho T, Kitabata H, Tsuda K, Tomobuchi Y, Akasaka T: Assessment of culprit lesion morphology in acute myocardial infarction: ability of optical coherence tomography compared with intravascular ultrasound and coronary angioscopy. J Am Coll Cardiol 2007, 50(10):933939. 19. Cheruvu C, Precious B, Naoum C, Blanke P, Ahmadi A, Soon J, Arepalli C, Gransar H, Achenbach S, Berman DS, Budoff MJ, Callister TQ, Al-Mallah MH, Cademartiri F, Chinnaiyan K, Rubinshtein R, Marquez H, DeLago A, Villines TC, Hadamitzky M, Hausleiter J, Shaw LJ, Kaufmann PA, Cury RC, Feuchtner G, Kim YJ, Maffei E, Raff G, Pontone G, Andreini D, Chang HJ, Min JK, Leipsic J: Long term prognostic utility of coronary CT angiography in patients with no modifiable coronary artery disease risk factors: Results from the 5 year follow-up of the CONFIRM International Multicenter Registry. J Cardiovasc Comput Tomogr. 2016, 10(1):22-7. - 21 -

ACCEPTED MANUSCRIPT

RI PT

20. Motoyama S, Sarai M, Harigaya H, Anno H, Inoue K, Hara T, Naruse H, Ishii J, Hishida H, Wong ND, Virmani R, Kondo T, Ozaki Y, Narula J: Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol 2009, 54(1):49-57. 21. Motoyama S, Kondo T, Sarai M, Sugiura A, Harigaya H, Sato T, Inoue K, Okumura M, Ishii J, Anno H, Virmani R, Ozaki Y, Hishida H, Narula J: Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J Am Coll Cardiol 2007, 50(4):319-326.

SC

22. Russo V, Zavalloni A, Bacchi Reggiani ML, Buttazzi K, Gostoli V, Bartolini S, Fattori R: Incremental prognostic value of coronary CT angiography in patients with suspected coronary artery disease. Circ Cardiovasc Imaging 2010, 3(4):351-359.

M AN U

23. Feuchtner G, Kerber J, Burghard P, Dichtl W, Friedrich G, Bonaros N, Plank F: The high-risk criteria low-attenuation plaque <60 HU and the napkin-ring sign are the most powerful predictors of MACE: a long-term follow-up study. Eur Heart J Cardiovasc Imaging. 2016 Aug 7. [Epub ahead of print]

TE D

24. Kashiwagi M, Tanaka A, Kitabata H, Tsujioka H, Kataiwa H, Komukai K, Tanimoto T, Takemoto K, Takarada S, Kubo T, Hirata K, Nakamura N, Mizukoshi M, Imanishi T, Akasaka T: Feasibility of noninvasive assessment of thin-cap fibroatheroma by multidetector computed tomography. JACC Cardiovasc Imaging 2009, 2(12):1412-1419.

EP

25. Tanaka A, Shimada K, Yoshida K, Jissyo S, Tanaka H, Sakamoto M, Matsuba K, Imanishi T, Akasaka T, Yoshikawa J: Non-invasive assessment of plaque rupture by 64-slice multidetector computed tomography-comparison with intravascular ultrasound. Circ J 2008, 72(8):1276-1281.

AC C

26. Nakazawa G, Tanabe K, Onuma Y, Yachi S, Aoki J, Yamamoto H, Higashikuni Y, Yagishita A, Nakajima H, Hara K: Efficacy of culprit plaque assessment by 64-slice multidetector computed tomography to predict transient no-reflow phenomenon during percutaneous coronary intervention. Am Heart J 2008, 155(6):1150-1157. 27. Toutouzas K, Karanasos A, Tsiamis E, Riga M, Drakopoulou M, Synetos A, Papanikolaou A, Tsioufis C, Androulakis A, Stefanadi E, Tousoulis D, Stefanadis C: New insights by optical coherence tomography into the differences and similarities of culprit ruptured plaque morphology in non-ST-elevation myocardial infarction and ST-elevation myocardial infarction. Am Heart J 2011, 161(6):1192-1199. - 22 -

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

28. Ino Y, Kubo T, Tanaka A, Kuroi A, Tsujioka H, Ikejima H, Okouchi K, Kashiwagi M, Takarada S, Kitabata H, Tanimoto T, Komukai K, Ishibashi K, Kimura K, Hirata K, Mizukoshi M, Imanishi T, Akasaka T: Difference of culprit lesion morphologies between ST-segment elevation myocardial infarction and non-ST-segment elevation acute coronary syndrome: an optical coherence tomography study. JACC Cardiovasc Interv 2011, 4(1):76-82.

- 23 -

ACCEPTED MANUSCRIPT

Figure legends

M AN U

SC

RI PT

Figure 1. An illustrative example of multi-modality imaging of coronary plaque in acute coronary syndrome: a lesion with intracoronary thrombus The left anterior descending coronary artery (A) shows a mixed plaque with large non-calcified portion (white arrowheads) and some calcified plaques more distally (black arrowheads). The multi-modality cross-sections at line b and c are displayed in B and C. From left to right: computed tomography images show a napkin-ring sign attenuation pattern (L = lumen). The circumferential outer rim (dashed blue line) has a higher contrast attenuation compared to the inner part of the plaque. Intravascular ultrasound images show a predominantly fibrous plaque (white arrowheads). Optical coherence tomography shows (mural) thrombus in both positions (white arrowheads) with a lipid-rich plaque behind the thrombus. * represents the shadow of the guidewire.

AC C

EP

TE D

Figure 2. An illustrative example of multi-modality imaging of coronary plaque in acute coronary syndrome: a lesion without intracoronary thrombus Invasive coronary angiography shows a tight lesion in the left anterior descending artery (#). The white dashed lines accompanied by small letters correspond to the IVUS and OCT cross-sections identified by corresponding capital letters. A multiplanar reformatted image of the left anterior descending coronary artery (B) with a mixed plaqe with large area with low attenuation (LV stands for left ventricle). The cross-sectional IVUS and OCT images corresponding to the white dashed lines in A and B show a coronary plaque with heavy calcification on corresponding places (white arrowheads). No intracoronary thrombus is observed. * represents the shadow of the guidewire.

- 24 -

ACCEPTED MANUSCRIPT TABLE 1 Patient characteristics

EP

TE D

M AN U

SC

Demographics Age (years) 68.3±10.7 Gender (male) 17 (56.7) Body mass index (kg/m2) 26.8 [24.4-28.9] Medical history Hypertension 16 (53.3) Diabetes 10 (33.3) Hypercholesterolaemia 10 (33.3) Current or previous smoker 13 (43.3) Family history 8 (26.7) Previous MI 4 (13.3) Previous PCI 6 (20.0) Previous CABG 2 (6.7) Previous CVA 5 (16.7) Laboratory values CK maximum (mg/L) 164.0 [86.5 - 301.0] CKMB maximum (mg/L) 21.0 [17.0 - 33.0] hs-TroponinT maximum (ng/L) [n=9] 192 [51 - 368] Troponin T maximum (µg/L) [n=21] 0.10 [0.03 - 0.20] Cholesterol (mmol/L) 4.9 [4.1 - 5.6] HDL - Cholesterol (mmol/L) 1.4 [1.1 - 1.6] LDL - Cholesterol (mmol/L) 3.1 [2.2 - 3.4] Computed Tomography Coronary Angiography characteristics Number of segments 15 [14 - 16] Plaques 8.5 [6.0 - 11.0] Non-obstructive plaques 6.0 [5.0 - 8.3] Obstructive plaques 2.0 [1.0 - 3.0] Non-calcified plaques 1.0 [0 - 1.3] Mixed plaques 2.0 [0 - 4.0] Calcified plaques 4.5 [1.0 - 7.0]

RI PT

N = 30

AC C

The data are mean±SD, median, IQR, or numbers (%). CABG = coronary artery bypass graft; CK = creatine kinase; CKMB = creatine kinase myocardial band; CVA = cerebrovascular accident; HDL = high density lipoprotein; IQR = interquartile range; LDL = low density lipoprotein; MI = myocardial infarction; PCI = percutaneous coronary intervention; SD = standard deviation.

- 25 -

ACCEPTED MANUSCRIPT TABLE 2 Association between thrombus on OCT and plaque characteristics on coronary CTA and IVUS Thrombus on OCT (n=20)

No thrombus on OCT (n=10)

9 (30.0) 5 (16.7) 11 (36.7) 5 (16.6) 17 (56.7) 8 (26.7)

9 (45.0) 5 (25.0) 10 (50.0) 2 (10.0) 13 (65.0) 5 (25.0)

0 (0) 0 (0) 1 (10.0) 3 (30.0) 4 (40.0) 3 (30.0)

8 (28.7)

6 (30.0)

2 (20.0)

(n=1083)

(n=97)

(n=986)

20 (20.6) 16 (16.5) 19 (19.6) 52 (53.6) 23 (23.7) 22 (22.7)

7 (0.7) 12 (1.2) 11 (1.1) 308 (31.2) 155 (15.7) 266 (26.9)

13 (13.4) 21 (21.7) 31 (31.96) 25 (25.8) 20 (20.6)

8 (0.8) 359 (36.4) 338 (34.3) 148 (15.0) 96 (9.7)

M AN U

27 (2.5) 28 (2.6) 30 (2.8) 360 (33.2) 178 (16.4) 288 (26.7)

RI PT

Cross-sectional level CT Thrombus Napkin-ring sign HU <30 Non-calcified Mixed Calcified IVUS Thrombus Fibrous Fibrocalcific Calcified Fatty

Total (n=30)

SC

Segment level CT Thrombus Napkin-ring sign HU <30 Non-calcified Mixed Calcified IVUS Thrombus

TE D

21 (1.9) 380 (35.1) 369 (34.0) 173 (16.0) 116 (10.7)

AC C

EP

The data are numbers (%). CTA = computed tomography angiography; HU = Houndsfield Units; IVUS = intravascular ultrasound; OCT = optical coherence tomography; TCFA = thin-cap fibroatheroma.

- 26 -

ACCEPTED MANUSCRIPT

OCT Associated with early lesions Fibrous Fibrocalcific

Normal

Total (all 3)

Associated with advanced lesions Lipid-rich

193 (75.1) 224 (62.2) 133 (74.7) 248 (86.1) 798

64 (24.9) 136 (37.8) 45 (25.3) 40 (13.9) 285

152 (59.1) 108 (30.0) 18 (10.1) 18 (6.2) 296

18 (7.0) 106 (29.4) 115 (64.6) 228 (79.2) 467

0 (0)

1 (3.6)

10 (35.7)

11 (39.3)

17 (60.7)

30 (66.7) 5 (1.3) 0 (0) 0 (0) 0 (0)

13 (28.9) 233 (61.3) 44 (11.9) 0 (0) 6 (5.2)

0 (0) 51 (13.4) 256 (69.4) 148 (85.5) 12 (10.3)

43 (95.6) 289 (76.0) 300 (81.3) 148 (85.5) 18 (15.5)

2 (4.4) 91 (24.0) 69 (18.7) 25 (14.5) 98 (84.5)

M AN U

SC

23 (9.0) 10 (2.8) 0 (0) 2 (0.7) 35

TE D

Modality and plaque composition CTA Normal Non-calcified Mixed Calcified Total CTA additional information Napkin ring sign IVUS Normal Fibrous Fibrocalcific Calcific Fatty

RI PT

TABLE 3. Plaque composition as assessed at coronary CTA and IVUS within atherosclerotic plaque categories as assessed at OCT

AC C

EP

The data are numbers (%). CTA = computed tomography angiography; HU = Houndsfield Units; IVUS = intravascular ultrasound; OCT = optical coherence tomography.

- 27 -

ACCEPTED MANUSCRIPT

Associated with early lesions

Associated with advanced lesions

257 (23.7) 360 (33.2) 178 (16.4) 288 (26.6)

193 (75.1) 224 (62.2) 133 (74.7) 248 (86.1)

64 (24.9) 136 (37.8) 45 (25.3) 40 (13.9)

45 (4.2) 380 (35.1) 369 (34.1) 173 (15.9) 116 (10.7)

43 (95.6) 289 (76.0) 300 (81.3) 148 (85.5) 18 (15.5)

Normal Fibrous Fibrocalcific Calcific Fatty

TE D

IVUS

Crude analysis OR p-value

0.33* 1.83 1.02 0.49

SC

Total

M AN U

OCT Modality and plaque composition CTA Normal Noncalcified Mixed Calcified

RI PT

TABLE 4 Association of coronary CTA and IVUS with lesions on OCT which are associated with early and advanced lesions

2 (4.4) 91 (24.0) 69 (18.7) 25 (14.5) 98 (84.5)

0.05* 6.77 4.94 3.63 117.06

0.571 0.000 0.780 0.000

Accounted for clustering OR p-value† 0.09* 4.04 1.91 2.16

0.000 0.000 0.098 0.049

0.000 0.02* 0.000 0.219 5.61 0.116 0.000 6.27 0.087 0.000 9.47 0.030 0.000 151.93 0.000 *Odds of the reference category is given †Bonferroni correction performed

AC C

EP

Odds ratio on having advanced lesions compared to the normal reference group, associated with early lesions, were calculated. The data are numbers (%). CTA = computed tomography angiography; IVUS = intravascular ultrasound; OCT = optical coherence tomography; OR = odds ratio.

- 28 -

ACCEPTED MANUSCRIPT TABLE 1 Patient characteristics N = 30

EP

TE D

M AN U

SC

RI PT

Demographics Age (years) 68.3±10.7 Gender (male) 17 (56.7) Body mass index (kg/m2) 26.8 [24.4-28.9] Medical history Hypertension 16 (53.3) Diabetes 10 (33.3) Hypercholesterolaemia 10 (33.3) Current or previous smoker 13 (43.3) Family history 8 (26.7) Previous MI 4 (13.3) Previous PCI 6 (20.0) Previous CABG 2 (6.7) Previous CVA 5 (16.7) Laboratory values CK maximum (mg/L) 164.0 [86.5 - 301.0] CKMB maximum (mg/L) 21.0 [17.0 - 33.0] hs-TroponinT maximum (ng/L) [n=9] 192 [51 - 368] Troponin T maximum (µg/L) [n=21] 0.10 [0.03 - 0.20] Cholesterol (mmol/L) 4.9 [4.1 - 5.6] HDL - Cholesterol (mmol/L) 1.4 [1.1 - 1.6] LDL - Cholesterol (mmol/L) 3.1 [2.2 - 3.4] Computed Tomography Coronary Angiography characteristics Number of segments 15 [14 - 16] Plaques 8.5 [6.0 - 11.0] Non-obstructive plaques 6.0 [5.0 - 8.3] Obstructive plaques 2.0 [1.0 - 3.0] Non-calcified plaques 1.0 [0 - 1.3] Mixed plaques 2.0 [0 - 4.0] Calcified plaques 4.5 [1.0 - 7.0]

AC C

The data are mean±SD, median, IQR, or numbers (%). CABG = coronary artery bypass graft; CK = creatine kinase; CKMB = creatine kinase myocardial band; CVA = cerebrovascular accident; HDL = high density lipoprotein; IQR = interquartile range; LDL = low density lipoprotein; MI = myocardial infarction; PCI = percutaneous coronary intervention; SD = standard deviation.

ACCEPTED MANUSCRIPT TABLE 2 Association between thrombus on OCT and plaque characteristics on coronary CTA and IVUS No thrombus on OCT (n=10)

9 (30.0) 5 (16.7) 11 (36.7) 5 (16.6) 17 (56.7) 8 (26.7)

9 (45.0) 5 (25.0) 10 (50.0) 2 (10.0) 13 (65.0) 5 (25.0)

0 (0) 0 (0) 1 (10.0) 3 (30.0) 4 (40.0) 3 (30.0)

8 (28.7)

6 (30.0)

2 (20.0)

(n=1083)

(n=97)

(n=986)

27 (2.5) 28 (2.6) 30 (2.8) 360 (33.2) 178 (16.4) 288 (26.7)

20 (20.6) 16 (16.5) 19 (19.6) 52 (53.6) 23 (23.7) 22 (22.7)

7 (0.7) 12 (1.2) 11 (1.1) 308 (31.2) 155 (15.7) 266 (26.9)

13 (13.4) 21 (21.7) 31 (31.96) 25 (25.8) 20 (20.6)

8 (0.8) 359 (36.4) 338 (34.3) 148 (15.0) 96 (9.7)

RI PT

Thrombus on OCT (n=20)

M AN U

Cross-sectional level CT Thrombus NRS HU <30 Non-calcified Mixed Calcified IVUS Thrombus Fibrous Fibrocalcific Calcified Fatty

Total (n=30)

SC

Segment level CT Thrombus NRS HU <30 Non-calcified Mixed Calcified IVUS Thrombus

21 (1.9) 380 (35.1) 369 (34.0) 173 (16.0) 116 (10.7)

AC C

EP

TE D

The data are numbers (%). CTA = computed tomography angiography; HU = Houndsfield Units; IVUS = intravascular ultrasound; NRS = napkin ring sign; OCT = optical coherence tomography; TCFA = thin-cap fibroatheroma.

ACCEPTED MANUSCRIPT

TABLE 3. Plaque composition as assessed at coronary CTA and IVUS within atherosclerotic plaque categories as assessed at OCT OCT Associated with early lesions Fibrous Fibrocalcific

Total (all 3)

Associated with advanced lesions Lipid-rich

RI PT

Normal

152 (59.1) 108 (30.0) 18 (10.1) 18 (6.2) 296

18 (7.0) 106 (29.4) 115 (64.6) 228 (79.2) 467

193 (75.1) 224 (62.2) 133 (74.7) 248 (86.1) 798

0 (0)

1 (3.6)

10 (35.7)

11 (39.3)

17 (60.7)

30 (66.7) 5 (1.3) 0 (0) 0 (0) 0 (0)

13 (28.9) 233 (61.3) 44 (11.9) 0 (0) 6 (5.2)

0 (0) 51 (13.4) 256 (69.4) 148 (85.5) 12 (10.3)

43 (95.6) 289 (76.0) 300 (81.3) 148 (85.5) 18 (15.5)

2 (4.4) 91 (24.0) 69 (18.7) 25 (14.5) 98 (84.5)

SC

23 (9.0) 10 (2.8) 0 (0) 2 (0.7) 35

M AN U

Modality and plaque composition CTA Normal Non-calcified Mixed Calcified Total CTA additional information Napkin ring sign IVUS Normal Fibrous Fibrocalcific Calcific Fatty

64 (24.9) 136 (37.8) 45 (25.3) 40 (13.9) 285

AC C

EP

TE D

The data are numbers (%). CTA = computed tomography angiography; HU = Houndsfield Units; IVUS = intravascular ultrasound; OCT = optical coherence tomography.

ACCEPTED MANUSCRIPT

TABLE 4 Association of coronary CTA and IVUS with lesions on OCT which are associated with early and advanced lesions OCT Total

Associated with early lesions

Associated with advanced lesions

257 (23.7) 360 (33.2) 178 (16.4) 288 (26.6)

193 (75.1) 224 (62.2) 133 (74.7) 248 (86.1)

64 (24.9) 136 (37.8) 45 (25.3) 40 (13.9)

45 (4.2) 380 (35.1) 369 (34.1) 173 (15.9) 116 (10.7)

43 (95.6) 289 (76.0) 300 (81.3) 148 (85.5) 18 (15.5)

2 (4.4) 91 (24.0) 69 (18.7) 25 (14.5) 98 (84.5)

M AN U

Normal Fibrous Fibrocalcific Calcific Fatty

0.33* 1.83 1.02 0.49

0.05* 6.77 4.94 3.63 117.06

SC

IVUS

Crude analysis OR p-value

RI PT

Modality and plaque composition CTA Normal Noncalcified Mixed Calcified

0.571 0.000 0.780 0.000

Accounted for clustering OR p-value ** 0.09* 4.04 1.91 2.16

0.000 0.000 0.098 0.049

0.000 0.02* 0.000 0.219 5.61 0.116 0.000 6.27 0.087 0.000 9.47 0.030 0.000 151.93 0.000 *Odds of the reference category is given ** Bonferroni correction performed

AC C

EP

TE D

Odds ratio on having advanced lesions compared to the normal reference group, associated with early lesions, were calculated. The data are numbers (%). CTA = computed tomography angiography; IVUS = intravascular ultrasound; OCT = optical coherence tomography; OR = odds ratio.

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT

Highlights -

The absence of plaque on CTA as assessed in vivo is associated with

CTA to exclude coronary artery disease. -

RI PT

normal findings or early stage of atherosclerosis on OCT, which supports using

Multiple different qualitative plaque features are associated with advanced

coronary lesions on OCT; accordingly, in case of coronary atherosclerosis it is

AC C

EP

TE D

M AN U

SC

not possible to differentiate between early and advanced focal lesions on CTA.