Relation Between Superficial Calcifications and Plaque Rupture: An Optical Coherence Tomography Study

Accepted Manuscript Relation Between Superficial Calcifications and Plaque Rupture: An Optical Coherence Tomography Study Yefei Zhan, MD, Yingying Zhang, MD, Jingbo Hou, MD, PhD, FACC, Guochang Lin, MD, PhD, Bo Yu, MD, PhD, FACC PII:

S0828-282X(17)30240-4

DOI:

10.1016/j.cjca.2017.05.003

Reference:

CJCA 2431

To appear in:

Canadian Journal of Cardiology

Received Date: 14 January 2017 Revised Date:

4 May 2017

Accepted Date: 4 May 2017

Please cite this article as: Zhan Y, Zhang Y, Hou J, Lin G, Yu B, Relation Between Superficial Calcifications and Plaque Rupture: An Optical Coherence Tomography Study, Canadian Journal of Cardiology (2017), doi: 10.1016/j.cjca.2017.05.003. 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 Relation Between Superficial Calcifications and Plaque Rupture: An Optical Coherence Tomography Study

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Short title: Calcifications and plaque rupture

Yefei Zhana,b#, MD, Yingying Zhanga#, MD, Jingbo Houa, MD, PhD, FACC,

Department of Cardiology, 2nd Affiliated Hospital of Harbin Medical University,

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Guochang Linc, MD, PhD, Bo Yua*, MD, PhD, FACC

Harbin, China; the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China

Department of Intensive Care Unit, Ningbo No.2 Hospital, Ningbo, China

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Center for Composite Materials, Harbin Institute of Technology

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b

Yefei Zhan and Yingying Zhang contributed equally to this work and should be

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considered co-first authors.

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*Corresponding author:

Bo Yu, MD, PhD, FACC, FESC Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China; the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education. 246 Xuefu Road, Nangang District, Harbin 150086, China. Tel.: (+86)-451-86605359; Fax: (+86)-451-86605180; E-mail: [email protected]

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ACCEPTED MANUSCRIPT Brief Summary We retrospectively analyzed 550 patients with acute coronary syndrome (ACS). A total of 78 patients with 78 culprit lipid-rich lesions having superficial calcifications on optical coherence tomography (OCT) images were included. We found that the

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smallest depth of calcium (CAL-DEP) in lipid-rich calcified plaque is a

morphological characteristic of a vulnerable plaque phenotype. A CAL-DEP less than or equal to 63 µm is the critical depth of calcification for lipid-rich calcified plaque

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rupture in patients with ACS.

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ACCEPTED MANUSCRIPT Abstract Background: There are several forms of calcium deposition, which play different roles in the stability of the coronary artery. It remains unknown whether certain

the same plaque in acute coronary syndrome (ACS).

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calcification morphological characteristics determine rupture of lipid-rich lesions in

Methods: We retrospectively analyzed 550 patients with ACS between May 2008 and October 2014, who had undergone pre-intervention optical coherence tomography

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(OCT) imaging examination. A total of 78 patients with 78 culprit lipid-rich lesions

having superficial calcifications on OCT images were included in this study, among

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which 45 were ruptured lesions with calcium (RC) and 33 were non-ruptured lipid-rich lesion with calcium (NRC). The smallest depth of calcium (CAL-DEP) was determined, and the morphology of the calcifications and plaques was analyzed during pre-intervention OCT.

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Results: The CAL-DEP was significantly thinner in RC than in NRC [50 (33, 63) µm vs. 110 (73, 208) µm, p < 0.001] and in myocardial infarction (MI) than in unstable angina pectoris (UAP) [57 (36, 78) µm vs. 85 (43, 140) µm, p = 0.045]. For lipid-rich

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calcified plaques, when CAL-DEP was less than 63 µm, the lipid-rich lesion was most

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vulnerable and prone to rupture (sensitivity = 77.8%, specificity = 81.8%, area under the curve: 0.804, p < 0.0001). Conclusions: Small CAL-DEP in lipid-rich calcified plaques is a morphological characteristic of a vulnerable plaque phenotype. A CAL-DEP less than or equal to 63 µm is the critical depth of calcification for lipid-rich calcified plaque rupture in patients with ACS.

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ACCEPTED MANUSCRIPT Introduction The presence of coronary artery calcification is often accompanied by a variety of inflammatory, metabolic, and genetic disorders, including hyperlipidemia, chronic kidney disease, diabetes, hyperparathyroidism, and osteoporosis.1 Calcification of the

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atherosclerotic plaque which is limited to the subintimal region can be observed as

early as the second decade of life. With the increase of age, the deposition of calcium

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increases as atherosclerosis progresses.2

The role of calcium in plaque remains unclear. In the American Heart Association

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(AHA) classification of coronary plaques, the fibrocalcific plaques are considered to be stable lesions.3 On the other hand, the presence of coronary artery calcification is a well-established marker of coronary plaque burden4 and is associated with a worse cardiovascular prognosis.5 Various forms of calcifications, such as spotty

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calcifications,6 calcified nodules,3 and microcalcifications in thin fibrous caps,7 are morphological characteristics of a vulnerable plaque phenotype. Whether there are other forms of calcification that have morphological characteristics of a vulnerable

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plaque phenotype remains unclear.

Plaque rupture, which occurs in lipid-rich lesions, is responsible for two thirds of acute coronary syndromes (ACS) and sudden cardiac death. It presents intimal discontinuity that exposes a tissue factor-like necrotic core and encourages thrombus formation. 8-10 This study aimed to find the correlation between calcifications and lipid-rich culprit plaque ruptures.

Intracoronary optical coherence tomography (OCT)11 is widely used to recognize the 4

ACCEPTED MANUSCRIPT detailed plaque morphology, and is the in vivo “gold standard” imaging modality due to its high resolution (10-15 µm),12 therefore allowing for a more detailed analysis of plaque morphology. The maximum depth of tissue penetration (1-2 mm) with OCT

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allows the detection of superficial calcification.

To better define the role of superficial calcification in coronary lipid-rich plaque

destabilization, we performed a detailed topographic study by OCT to identify and

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compare specific morphological characteristics of ruptured lesions with calcium (RC)

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and non-ruptured lipid-rich lesion with calcium (NRC) in patients with ACS.

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ACCEPTED MANUSCRIPT Methods Study population We retrospectively reviewed 550 patients with ACS treated between May 2008 and October 2014, who had undergone pre-intervention optical coherence tomography

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(OCT) imaging examination. Among the lesions of these patients, 224 culprit plaques contained calcium, and 410 plaques were ruptured or were lipid-rich lesions; only 132 culprit plaques in 132 ACS patients having both calcifications and ruptured or

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lipid-rich lesions were included in the study.

ACS included ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina pectoris (UAP). STEMI was defined as a continuous chest pain that lasted more than

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30 minutes, before arrival at the hospital within 12 hours of the onset of symptoms, ST-segment elevation greater than 0.1 mV in more than two contiguous leads or new

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left bundle-branch block on the 12-lead electrocardiogram (ECG), and elevated circulating levels of cardiac markers (creatine kinase-myocardial band or troponin

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T/I).

NSTEMI was determined as the existence of clinical manifestations of ischemia with increased levels of serum cardiac markers without ST-segment elevation on the ECG. UAP was determined as having newly developed or accelerating ischemic symptoms within two weeks. The culprit lesion was recognized according to echocardiogram, ECG, stress test or coronary angiogram. 6

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Seventy-eight coronary calcified lesions in 78 patients were part of this study, and the remaining 54 patients were excluded (Fig 1). The exclusion criteria were as follows: (1) lesions were fissured (n = 22) or dissected (n = 3) in OCT images; (2) a previous

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stent implantation was found in the culprit vessel (n = 18); and (3) a large residual

thrombus (n = 9) or poor image quality (n = 2) that interfered with image analysis.

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Quantitative coronary angiographic analysis

Quantitative coronary angiography was conducted using off-line software (CAAS

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5.10.1, Pie Medical Imaging BV, Maastricht, Netherlands). The reference diameter, minimal luminal diameter, and percent diameter stenosis were calculated.

OCT imaging and analysis

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The OCT imaging was performed using the time domain OCT (TD-OCT) (M2/M3 ImageWire®; LightLab Imaging, Westford, MA, USA) or frequency domain OCT (FD-OCT) (C7 Dragonfly®, St Jude Medical, St Paul, MN, USA). All OCT data were

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analyzed using the proprietary offline software (LightLab Imaging) by two

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independent investigators (YF Z and YY Z) who were blinded to the clinical presentations and lesion characteristics. When there was discordance between the two observers, another reading was obtained from a third independent investigator (JB H), and a consensus interpretation was reached.

Identification of two separate plaques in the same vessel required a 5 mm or greater reference segment between them; if not, they were considered one long lesion.13, 14 Lipid deposit was semi-quantified by measuring the lipid arc. Lipid-rich plaque was 7

ACCEPTED MANUSCRIPT defined as lipid arc greater than 90°.15 In the lipid-rich plaque, lipid max arc was noted. Plaque rupture was defined as the presence of fibrous-cap discontinuity and a cavity formation within the plaque. Fibrous cap thickness (FCT) was measured at its thinnest part three times, and the average value was calculated in NRC. For RC, the

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thinnest part of FCT was measured at the thinnest part of the remnant of the disrupted fibrous cap. These measurements were performed three times for each subject, and the average value was calculated (Fig 2). Plaque length was the length of the culprit

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plaque evaluated on the longitudinal view. Calcific plaque was identified by the

presence of well-delineated, low back-scattering heterogeneous regions in the OCT

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images. OCT only detected superficial calcifications but not those in a deep position or behind a lipid plaque. The calcium max arc was the maximum of calcium arc in each culprit lesion. Calcium length was the total length of calcium in the culprit plaque, evaluated on the longitudinal view. The smallest depth of calcium (CAL-DEP)

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was defined as the shortest distance measurable between the leading edge of the calcified plaque to the lumen boundary, which was measured three times per subject, and the average value was calculated (Fig 2). Macrophage accumulation on the OCT

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images was defined as an increased signal intensity within the plaque, accompanied

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by heterogeneous backward shadows. Microchannel was defined as a black hole with a diameter of 50 to 300 µm within a plaque that was present on at least three consecutive frames. Existence of cholesterol crystals was defined by the presence of linear and highly reflecting structures within the plaques. Thrombus was defined as a mass with a diameter greater than 250 mm attached to the luminal surface or floating within the lumen.

Statistical analysis 8

ACCEPTED MANUSCRIPT The analysis was performed using SPSS 17.0 (SPSS, Chicago, IL, USA). Categorical variables were presented as counts and/or percentages and were statistically analyzed using chi-square tests. All continuous variables were expressed as mean ± standard deviation (SD) for normally distributed variables or median (25th–75th percentile) for

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non-parametric data. The mean values between two groups were statistically

evaluated using Student’s t tests. Differences between non-parametric continuous variables were evaluated using the Mann-Whitney U test. Receiver operating

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characteristic (ROC) analysis was performed to assess the best cutoff value of

CAL-DEP to predict plaque rupture using Medcalc (Medcalc Software, Mariakerke,

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Belgium) as the value with the highest sum of sensitivity and specificity. A p value

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less than 0.05 was regarded as statistically significant.

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ACCEPTED MANUSCRIPT Results Among the vessels examined in all 78 patients, 45 were diagnosed as RC by OCT (STEMI, 25; NSTEMI, 1; UAP, 19), and 33 were diagnosed as NRC (STEMI, 1; NSTEMI, 1; UAP, 31). A summary of the plaque identification and diagnosis is shown

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in Figure 1.

Study population

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Table 1 shows a comparison of baseline clinical characteristics between RC and NRC patients. There were no statistically significant differences with respect to age, gender,

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and other important coronary risk factors. There were statistical differences in two laboratory findings between the RC and the NRC groups [triglyceride: 144 (117, 210) mg/dL vs. 132 (88, 162) mg/dL, p = 0.046; C-reaction protein: 7.4 (3.3, 13.5) mg/L vs. 4.8 (1.5, 8.0) mg/L, p = 0.028]. There was also a significant difference in clinical

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presentation between these two groups. In this study, 57.8% patients in the RC group had MI compared with only 6.1% in the NRC group (p < 0.005).

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Angiographic findings

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The distribution of plaques in the three coronary arteries of all 78 patients was shown as follows: 56.4% of the plaques were located in the left anterior descending artery, 16.7% in the left circumflex, and 26.9% in the right coronary artery. There was no significant difference between these two groups in distribution. The quantitative coronary analysis data and lesion distribution are listed in Table 1. No significant differences in reference diameter were observed between the two groups; however, the RC group had smaller minimum lumen diameter (0.80 ± 0.33 mm vs. 1.17 ± 0.51 mm, p = 0.001) and higher percent diameter stenosis than the NRC group (77 ± 9 % 10

ACCEPTED MANUSCRIPT vs. 63 ± 12 %, p < 0.001).

OCT findings

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The OCT findings are shown in Table 1 and Table 2.

CAL-DEP was smaller in the RC group than in the NRC group [50 (33, 63) µm vs. 110 (73, 208) µm, p < 0.001]. The numbers of RC and NRC in association with

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CAL-DEP are shown in Figure 3A. No differences in calcium max arc, calcium length, lipid max arc, FCT, and plaque length and in the incidence of macrophage and

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cholesterol crystals were observed between the RC and NRC groups. However, compared with the NRC group, the incidence of microchannels and thrombus of the RC group was significantly higher (40.0 % vs. 18.2 %, p < 0.05; 82.2 % vs. 0 %, p < 0.001). Thus, OCT shows that the RC group has smaller incidence of CAL-DEP and

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higher incidence of microchannels and thrombus than the NRC group (Table 1).

CAL-DEP had a potentially predictive value for RC, and receiver-operating

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characteristic (ROC) curve analysis showed an area under the curve (AUC) of 0.804

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(95% CI: 0.699 to 0.886, p < 0.0001, Fig 3, B). For lipid-rich calcified plaque, when CAL-DEP was smaller than 63 µm, the lipid-rich lesion was most vulnerable and prone to rupture (Table 3).

There were no differences between the MI and UAP groups in all OCT finding indices, except CAL-DEP and thrombi. CAL-DEP [57 (36, 78) µm vs. 85 (43, 140) µm, p = 0.045] was smaller, and the incidence of thrombus was significantly higher (75.0% vs. 32.0%, p < 0.05) in the MI group than in the UAP group. OCT shows that the MI 11

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group has smaller CAL-DEP and more thrombi than the UAP group (Table 2).

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ACCEPTED MANUSCRIPT Discussion To date, three main types of vascular calcification have been reported: infantile calcification, medial Mönckeberg arterial calcification, and intimal calcification.16 Among these calcifications, intimal calcification is related to coronary

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atherosclerosis16 and is the focus of our article. Superficial calcification that is

positioned close to the lumen is an intimal calcification. Calcifications in different

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locations of lesions play different roles in the stability of the coronary artery.

We selected only plaques that had both lipid-rich lesions/ruptured lipid-rich lesions

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(ruptured plaque) and calcifications (n = 132) as observed in OCT imaging examination from 550 ACS patients (between May 2008 and October 2014) and excluded those ACS patients who did not meet the criteria (n = 418). These inclusion and exclusion data suggested that approximately one quarter of ACS patients (24%)

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might have both lipid-rich lesion and ruptured lipid-rich lesion (ruptured plaque) and calcifications in the one plaque, and in our study, we found that superficial

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calcification in lipid-rich lesions is a potential risk factor for plaque rupture.

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Lipid pooling plays a leading role in exposing lipids to the flowing blood, the thrombogenic parts of the atherosclerotic plaque, which will subsequently activate the clotting cascade including platelet adhesion, activation, and aggregation. These activations lead to thrombosis with an abrupt luminal compromise. Such plaque rupture is believed to cause most MI and stroke.17 A variety of biomechanical factors including hemodynamic shear stresses, turbulent pressure fluctuations, transient compression, mechanical shear stresses, sudden increase in intraluminal pressure, and rupture of the vasa vasorum have been postulated to play a role in plaque disrupture.18 13

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The mechanisms that promote a superficial calcification, particularly those with a CAL-DEP of 63 µm or less, and that easily rupture with an underlying ruptive

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lipid-rich lesion, are probably the following:

1) Our research showed that the depth of the calcification was tightly associated with the plaque stability. Superficial stiff calcium deposit exerts an adverse effect and

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increases the shear force.19, 20 The more superficial the calcification is, the less buffer force that fibrous tissue above it can provide; this results in higher stress imposed by

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blood flow. Thus, we speculate that as long as the superficial calcium is beside the lipid core, the change in shear force is undoubtedly the rupture risk factor in the lipid-rich plaque, regardless of whether the calcium is in the upstream or downstream

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or in the same cross section of the lipid core.

2) Failure stress, known as von Mises or maximal principal stress, tends to occur at the interface between materials of different stiffness, and causing rupture. In our study,

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approximately 57.8% of lesions had a calcium portion clinging to a rupture location. Calcified atherosclerotic plaque is at least four to five times stiffer than cellular

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plaque,21 and much stiffer than lipid core. Thus, a greater deposition of calcium within an artery makes the interface stiffer and less expandable, therefore increasing the instability of the interface artery segments. In lipid lesions, because soft lipid pools or fibrous tissue and stiff calcium in the diseased vessel are unable to bear significant stresses, the high stress develops between these regions, and any change in tensile strain that occurs at the interface between the calcified and lipid pool can further promote the rupture at the lipid-rich lesion with calcium. 14

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3) Vascular calcification is triggered by disordered calcium and phosphate homeostasis or by active processes involving inflammatory cytokines, macrophages, and other signals, which are controlled by complex regulatory networks. OCT

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imaging has been proposed as a high-resolution imaging modality that can identify microstructures in atherosclerotic plaques.22, 23 Our study showed that the

microchannels were more frequently present in RC than in NRC, and increased

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vascularity may provide a source for recruitment of inflammatory cells into the

plaque.24, 25 In addition, a rupture of the thin-walled vasa in the plaque intima may

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lead to hemorrhage with a secondary plaque rupture,9 as evidenced by the observation that a total microvessel density was increased in the ruptured plaques when compared with that in the non-ruptured plaques.24 As a result, microchannels in plaques may

Study limitations

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offer help in identifying the vulnerability of calcification.

First, this study was a retrospective, single-center study, raising the possibility of

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selection bias. In addition, OCT cannot detect a calcified plaque in a deep position or

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behind a lipid plaque because of its limited scanning diameter. Thus, the amount of calcification may be underestimated in OCT images.

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ACCEPTED MANUSCRIPT Conclusions Small CAL-DEP in lipid-rich calcified plaque is a morphological characteristic of a vulnerable plaque phenotype. A CAL-DEP 63 µm or less is the critical cutoff point of calcification for lipid-rich calcified plaque rupture in patients with ACS. Future

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studies are required to validate whether this cutoff point can predict plaque rupture and clinical events or can serve as a therapeutic target for patients with coronary

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artery disease.

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ACCEPTED MANUSCRIPT Funding Sources Dr. Yu received a grant from the National Natural Science Foundation of China (grant

Conflict of Interest

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The authors declare that they have no conflict of interest.

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contract number: 81171430, 8130033).

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ACCEPTED MANUSCRIPT Reference 1.

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Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons From

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Sudden Coronary Death : A Comprehensive Morphological Classification

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Scheme for Atherosclerotic Lesions. Arteriosclerosis, Thrombosis, and Vascular

Sangiorgi G, Rumberger JA, Severson A, et al. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in

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humans: a histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol 1998;31:126-33. 5.

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of first unheralded acute myocardial infarction by electron-beam computed

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tomography. Circulation 2000;101:850-5. Kataoka Y, Wolski K, Uno K, et al. Spotty calcification as a marker of

accelerated progression of coronary atherosclerosis: insights from serial intravascular ultrasound. J Am Coll Cardiol 2012;59:1592-7.

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Vengrenyuk Y, Carlier S, Xanthos S, et al. A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps. Proc Natl Acad Sci U S A 2006;103:14678-83. 18

ACCEPTED MANUSCRIPT 8. 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;108:1664-72. Shah PK. Mechanisms of plaque vulnerability and rupture. Journal of the American College of Cardiology 2003;41:S15-S22.

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10. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and

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rupture. Circ Res 2014;114:1852-66.

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11. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science

12. Jang IK, Tearney G, Bouma B. Visualization of tissue prolapse between coronary stent struts by optical coherence tomography: comparison with

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intravascular ultrasound. Circulation 2001;104:2754.

13. Hong MK, Mintz GS, Lee CW, et al. Comparison of coronary plaque rupture between stable angina and acute myocardial infarction: a three-vessel

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intravascular ultrasound study in 235 patients. Circulation 2004;110:928-33.

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14. 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;61:1041-51.

15. Tanaka A, Imanishi T, Kitabata H, et al. Lipid-rich plaque and myocardial perfusion after successful stenting in patients with non-ST-segment elevation acute coronary syndrome: an optical coherence tomography study. Eur Heart J 19

ACCEPTED MANUSCRIPT 2009;30:1348-55. 16. Otsuka F, Sakakura K, Yahagi K, Joner M, Virmani R. Has our understanding of calcification in human coronary atherosclerosis progressed? Arterioscler

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Thromb Vasc Biol 2014;34:724-36. 17. Virmani R, Ladich ER, Burke AP, Kolodgie FD. Histopathology of carotid atherosclerotic disease. Neurosurgery 2006;59:S219-27; discussion S3-13.

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18. Cheng GC, Loree HM, Kamm RD, Fishbein MC, Lee RT. Distribution of

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circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation. Circulation 1993;87:1179-87. 19. Abedin M, Tintut Y, Demer LL. Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol 2004;24:1161-70.

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20. Sage AP, Tintut Y, Demer LL. Regulatory mechanisms in vascular calcification. Nat Rev Cardiol 2010;7:528-36.

21. Lee RT, Grodzinsky AJ, Frank EH, Kamm RD, Schoen FJ. Structure-dependent

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dynamic mechanical behavior of fibrous caps from human atherosclerotic

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plaques. Circulation 1991;83:1764-70. 22. Yabushita H, Bouma BE, Houser SL, et al. Characterization of human atherosclerosis by optical coherence tomography. Circulation 2002;106:1640-5.

23. Jang IK, Tearney GJ, MacNeill B, et al. In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography. Circulation 2005;111:1551-5. 24. Tenaglia AN, Peters KG, Sketch MH, Jr., Annex BH. Neovascularization in 20

ACCEPTED MANUSCRIPT atherectomy specimens from patients with unstable angina: implications for pathogenesis of unstable angina. Am Heart J 1998;135:10-4. 25. O'Brien ER, Garvin MR, Dev R, et al. Angiogenesis in human coronary

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atherosclerotic plaques. Am J Pathol 1994;145:883-94.

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ACCEPTED MANUSCRIPT Figure legends Figure 1. Summary of lesions diagnosis A total of 132 culprit calcifications were identified in 132 patients with ACS.

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Fifty-four cases were excluded after application of exclusion criteria. Ultimately, 45 RC and 33 NRC were identified from 78 culprit calcification lesions. ACS = acute coronary syndrome; RC = ruptured calcifications; NRC = nonruptured lipid-rich

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plaque combining calcification; STEMI = ST-segment elevation myocardial

unstable angina pectoris.

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infarction; NSTEMI = non–ST-segment elevation myocardial infarction; UAP =

Figure 2. Representative optical coherence tomography images

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Representative measurements of ruptured (I) and non-ruptured (II) thinnest cap thickness (B in the in the yellow box) and shortest depth of calcium (CAL-DEP, A in the blue box).☆ = the presence of calcific plaque; * = shadow caused by the wire

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artifact; ∆ = cavity (after plaque rupture).

Figure 3.

A: Number of plaques in association with CAL-DEP. Bar graphs show the distribution of ruptured and non-ruptured plaques according to the CAL-DEP. B: Receiver operating characteristic (ROC) curves for measurements of CAL-DEP for prediction of plaque rupture. ROC curves were plotted with sensitivity on the y-axis and 1-specificity on the x-axis. Note that the area under the curve (AUC) 22

ACCEPTED MANUSCRIPT showed that CAL-DEP was a good parameter for classifying ruptured plaque. H0: AUC = 0.5. An AUC of 0.5 indicated equality between true positive and false positive test results. A p value < 0.05 was considered significant. CAL-DEP =

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smallest depth of calcium.

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CAL-DEP = smallest depth of calcium.

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ACCEPTED MANUSCRIPT Table 1. Comparison of basal characteristics, angiographic findings and OCT findings between RC and NRC Non-Rupture Plaque

(n=45)

(n=33)

Age, year

60.0 ± 8.5

60.6 ± 9.3

Men (%)

36 (80.0)

21 (63.3)

MI history (%)

8 (17.8)

6 (18.2)

PCI history (%)

9 (20.0)

7 (21.2)

1.000

Hypertension (%)

26 (57.8)

19 (57.6)

1.000

Diabetes (%)

15 (33.3)

12 (36.4)

0.813

Smoking (%)

17 (37.8)

12 (36.4)

1.000

159.5 ± 38.6

175.3 ± 40.0

0.083

144 (117, 210)

132 (88, 162)

0.046*

49.1 (44.9, 53.6)

53.0 (40.0, 61.3)

0.215

LDL-C, mg/dL

89.2 ± 40.9

90.1 ± 24.7

0.914

FPG, mmol/L

6.7 (5.6, 9.2)

5.8 (5.4, 7.3)

0.127

GHb, %

6.1 (5.6, 7.6)

6.2 (5.8, 7.0)

0.851

CRP, mg/L

7.4 (3.3, 13.5)

4.8 (1.5, 8.0)

0.028*

26 (57.8)

2 (6.1)

＜0.001*

TG, mg/dL

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TC, mg/dL

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Laboratory findings

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Basal characteristics

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HDL-C, mg/dL

P

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Rupture Plaque

0.757

0.127

1.000

Clinical presentation MI (%)

ACCEPTED MANUSCRIPT STEMI (%)

25 (55.6)

1 (3.0)

NSTEMI (%)

1 (2.2)

1 (3.0)

19 (42.2)

31 (93.9)

LAD (%)

25 (55.6)

19 (57.6)

LCX (%)

9 (20.0)

4 (12.1)

RCA (%)

11 (24.4)

10 (30.3)

UAP (%)

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QCA data

0.617

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Lesion location

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Angiographic findings

0.80 ± 0.33

1.17 ± 0.51

0.001*

RD,mm

3.43 ± 0.77

3.18 ± 0.77

0.153

DS, %

77 ± 9

63 ± 12

＜0.001*

239 (198, 360)

252 (159, 272)

0.389

91 ± 41

98 ± 41

0.472

13.1 ± 4.9

11.2± 4.4

0.065

Calcium max arc, °

83 (60, 109)

76 (55, 115)

0.940

CAL-DEP, µm

50 (33, 63)

110 (73, 208)

＜0.001*

Calcium length, mm

3.7 (2.2, 7.7)

3.5 (2.3, 6.2)

0.568

Macrophage (%)

35 (77.8)

25 (75.8)

1.000

Microchannel (%)

18 (40.0)

6 (18.2)

0.049*

Cholesterol (%)

13 (28.9)

10 (30.3)

1.000

OCT findings

FCT, µm

EP

Lipid max arc, °

TE D

MLD, mm

AC C

Plaque length, mm

ACCEPTED MANUSCRIPT Thrombus (%)

37 (82.2)

0 (0)

＜0.001*

Values are n (%) or mean ± SD. *P < 0.05. MI = myocardial infarction; STEMI = ST-segment elevation myocardial infarction;

RI PT

NSTEMI = non-ST-segment elevation myocardial infarction; UAP = unstable angina pectoris; PCI = percutaneous coronary intervention; TC = total cholesterol; TG =

triglyceride; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density

SC

lipoprotein cholesterol; FPG = fasting plasma glucose; A1C = glycosylated

M AN U

hemoglobin; CRP = C-reactionprotein; LAD = left anterior descending artery; LCX = left circumflex artery; RCA = right coronary artery; QCA = quantitative coronary angiogram analysis; MLD = minimum lumen diameter; RD = reference diameter; DS = diameter stenosis; FCT = minimum fibrous cap thickness; CAL-DEP =

AC C

EP

TE D

smallest depth of calcium.

ACCEPTED MANUSCRIPT Table 2. Comparison of OCT findings between MI and UA MI

UAP

(n=28)

(n=50)

Lipid max arc , °

236 (118, 349)

249 (182, 297)

FCT, µm

96 ± 49

92 ± 36

0.751

Plaque length, mm

12.6 ± 3.8

12.1 ± 5.2

0.671

Calcium max arc , °

84 (58, 115)

78 (59, 107)

0.685

CAL-DEP, µm

57 (36, 78)

85 (43, 140)

0.045*

Calcium length , mm

3.5 (2.3, 6.5)

3.6 (2.2, 7.3)

0.900

Macrophage (%)

25 (89.3)

35 (70.0)

0.091

Microchannel (%)

12 (42.9)

12 (24.0)

0.124

Cholesterol (%)

7 (25.0)

16 (32.0)

0.609

16 (32.0)

＜0.001*

21 (75.0)

EP

Values are n (%) or mean ± SD. *P < 0.05.

AC C

Abbreviations as in Table 1.

0.875

RI PT

SC

M AN U

TE D

Thrombus (%)

P

ACCEPTED MANUSCRIPT

≤63µm

0.596

Sensitivity

Specificity

+LR

(95% CI)

(95% CI)

(95% CI)

(95% CI)

77.8

81.8

SC

CAL-DEP

YI

4.28

0.27

M AN U

Cutoff

RI PT

Table 3. Determination of cut-off values of CAL-DEP for detection of ruptured calcified plaques

(62.9-88.8)

(64.5-93.0)

AC C

EP

TE D

YI = Youden Index; CI = confidence interval; LR = Likelihood Ratio.

(2.0-9.0)

-LR

(0.2-0.5)

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

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT