J A C C : C A R D I O V A S C U L A R I M A G I N G V O L . 1 0 , N O . 8 , 2 0 1 7

ª 2 0 1 7 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N

P U B L I S H E D B Y E L S E V I E R

I S S N 1 9 3 6 - 8 7 8 X / $ 3 6 . 0 0

h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j c m g . 2 0 1 7 . 0 5 . 0 1 3

Prevalence, Predictors, and ClinicalPresentation of a Calcified Nodule as

Assessed by Optical Coherence TomographyTetsumin Lee, MD,a,b Gary S. Mintz, MD,a Mitsuaki Matsumura, BS,a Wenbin Zhang, MD,a,b Yang Cao, MD,a,b

Eisuke Usui, MD,c Yoshihisa Kanaji, MD,c Tadashi Murai, MD,c Taishi Yonetsu, MD,c Tsunekazu Kakuta, MD, PHD,c

Akiko Maehara, MDa,b

ABSTRACT

Fro

Co

Iba

rec

Bo

spe

thi

Ma

OBJECTIVES This study sought to determine the anatomic characteristics and clinical presentation associated with

a calcified nodule (CN) as assessed by optical coherence tomography.

BACKGROUND CN is an unusual but demonstrable cause of acute coronary syndromes (ACS).

METHODS We studied 889 de novo culprit lesions in 889 patients (48% ACS) who underwent optical coherence

tomography before intervention. CN was defined as an eruptive accumulation of nodular calcification (small fractured

calcifications). Using quantitative coronary angiography, the change in the angle of the lesion between diastole

and systole was measured (angiographic D angle).

RESULTS CN was seen in 4.2% of all lesions and was located more frequently in the ostial or mid right coronary artery.

Hemodialysis (odds ratio: 4.0; 95% confidence interval: 1.1 to 13.4; p ¼ 0.04), in-lesion angiographic D angle (odds ratio:

1.09; 95% confidence interval: 1.05 to 1.14; p< 0.001), and maximum calcium arc by optical coherence tomography (odds

ratio: 1.02; 95% confidence interval: 1.01 to 1.02; p< 0.001) were significantly associated with the presence of a CN in the

multivariable model. When we compared CNs in patients with ACS versus stable angina presentation, there was a smaller

minimum lumen area (1.04 mm2 [first quartile, third quartile: 0.69, 1.26] vs. 1.61 [first quartile, third quartile: 1.03,

2.06] mm2; p¼ 0.02) accompanied by more thrombus (82.4% vs. 20.0%; p< 0.001) in CN lesions with ACS presentation.

In lesions with severe calcification (maximum calcium arc >180�), 30% of ACS culprit lesions contained a CN, and the

presence of a CN was associated with ACS presentation independent of other vulnerable plaque morphologies.

CONCLUSIONS The presence of a CN was associated with severe calcification and larger hinge movement of the

coronary artery (especially ostial and mid right coronary artery). One-third of the underlying plaque morphology

of severely calcified culprit lesions in patients with ACS was caused by a CN. (J Am Coll Cardiol Img 2017;10:883–91)

© 2017 by the American College of Cardiology Foundation.

P revious pathology reports showed that mostacute coronary syndromes (ACS) events arecaused by sudden luminal thrombosis:

approximately 60% caused by plaque rupture, 30%caused by plaque erosion, and a small portion

m the aClinical Trials Center, Cardiovascular Research Foundation, New

lumbia University Medical Center, New York, New York; and cCardiovas

raki, Japan. Dr. Mintz is a consultant for or has received honoraria fro

eived fellowship/grant support from Volcano, St. Jude, and Boston Scien

ston Scientific and St. Jude Medical; is a consultant for Boston Scien

aker fees from St. Jude Medical. All other authors have reported that th

s paper to disclose. H. Vernon Anderson, MD, served as the Guest Editor

nuscript received March 1, 2017; revised manuscript received May 9, 201

resulting from a calcified nodule (CN) defined as aneruptive accumulation of small nodular calcifications(1,2). However, it was not clear whether a CN was aunique morphology for ACS presentation or whetherit can be benign. In the PROSPECT (Providing

York, New York; bNewYork-Presbyterian Hospital/

cular Medicine, Tsuchiura Kyodo General Hospital,

m Boston Scientific, ACIST, and Volcano; and has

tific. Dr. Maehara has received grant support from

tific and OCT Medical Imaging; and has received

ey have no relationships relevant to the contents of

for this article.

7, accepted May 19, 2017.

FIGURE 1 Study Flow Diagram

2711 lesions

1487 lesions in 11

1069 lesions in 889

889 de novo culprit lesOCT im

37 culprit lesions with

Among a total of 1,487 lesions in

de novo culprit lesions in 889 pa

tigated in the present study. The

to the OCT findings: culprit lesion

OCT ¼ optical coherence tomog

SEE PAGE 892

ABBR EV I A T I ON S

AND ACRONYMS

ACS = acute coronary

syndromes

CI = confidence interval

CN = calcified nodule

IVUS = intravascular

ultrasound

OCT = optical coherence

tomography

OR = odds ratio

RCA = right coronary artery

STEMI = ST-segment elevation

myocardial infarction

Lee et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 8 , 2 0 1 7

Calcified Nodule Assessed by OCT A U G U S T 2 0 1 7 : 8 8 3 – 9 1

884

Regional Observations to Study Predictorsof Events in the Coronary Tree) study using3-vessel grayscale and intravascular ultra-sound (IVUS)–virtual histology, Xu et al. (3)reported at least 1 nonculprit CN in 30% ofpatients, and most were benign. AlthoughIVUS has been widely used to assess coronarycalcification, IVUS does not have sufficientresolution to visualize small nodular calcifi-cations. Compared with IVUS, intravascularoptical coherence tomography (OCT) has agreater resolution, can detect red and whitethrombus, and can penetrate calcium, thushaving the potential to characterize the de-tails of coronary calcification and, in partic-

ular, a CN (4–7). We sought to use OCT to evaluatethe anatomic characteristics and clinical presenta-tions that are associated with the presence of a CN.

METHODS

STUDY POPULATION. This was a single-center,retrospective observational study at TsuchiuraKyodo General Hospital, Ibaraki, Japan. From October2008 to May 2015 we studied 889 culprit de novocoronary artery lesions in 889 patients, of whom 428presented with ACS (169 ST-segment elevationmyocardial infarction [STEMI], 191 non-STEMI,

in 2059 patients that were treated with PCI

23 patients that underwent pre-PCI OCT imaging

268 in-stent restenosis

27 stent thrombosis

14 graft lesions

95 balloon angioplasty before OCT imaging

14 insufficient image quality

patients that underwent pre-PCI OCT imagingfor de novo lesions

ions in 889 patients that underwent pre-PCIaging (1 lesion per patient)

CN 852 culprit lesions without CN

180 (secondary) lesions that were not determined(clinically) to be the culprit lesion

1224 lesions with no pre-PCI OCT imaging

1,123 patients that underwent pre-PCI OCT imaging, 889

tients that underwent pre-PCI OCT imaging were inves-

lesions were divided into the following 2 groups according

s with or without calcified nodule. CN¼ calcified nodule;

raphy; PCI ¼ percutaneous coronary intervention.

68 unstable angina) and 461 presented with stableangina (Figure 1). Lesions with anticipated difficultyin advancing the OCT catheter, such as lesions withsevere narrowing, tortuosity, or severe calcification,were excluded and not imaged by the operators. Incases with angiographically significant thrombus,thrombectomy was performed before OCT imaging.All patients provided written informed consentbefore imaging and subsequent intervention forpossible data use in future studies.

CORONARY ANGIOGRAPHIC ANALYSIS. Quantitativecoronary angiography was performed using QCA-CMS(Medis Medical Imaging Systems bv, Leiden, theNetherlands). Calibration was performed using theguiding catheter;minimum lumen diameter, referencediameter, and lesion lengthweremeasured in diastolicframes from orthogonal projections. A change in theangiographic angle of the lesion (D angle) was definedas the difference in the angle between systole anddiastole (Figures 2A to 2D) using the view withmaximum D angle (8). Angiographic calcification wasclassified as none or mild, moderate, or severe at thetarget lesion site. Moderate calcification was definedas radiopacities noted only during the cardiac cyclebefore contrast injection, whereas severe calcificationwas defined as radiopacities seen without cardiacmotion, usually affecting both sides of the arteriallumen (9). Coronary tortuosity was defined as 2 bends>75� or 1 bend >90� proximal to the target lesion.

OCT IMAGE ACQUISITION AND ANALYSIS. A time-domain OCT (M2/M3 Cardiology Imaging System,LightLab Imaging Inc., Westford, Massachusetts)(n ¼ 486), frequency-domain OCT (C7 or C7-XR OCTIntravascular Imaging System, St. Jude Medical, St.Paul, Minnesota) (n ¼ 403), or optical frequencydomain imaging system (Terumo Corporation, Tokyo,Japan) was used. The technique for OCT imaging hasbeen described previously (10–12). In brief, using atime-domain OCT system, an occlusion balloon (He-lios, LightLab Imaging Inc.) was advanced to a posi-tion proximal to the lesion and inflated up to 0.4 to0.6 atm during image acquisition. The imaging corewas advanced at least 10 mm distal to the lesion, andautomated pull-back was initiated from distal toproximal at 1.0 mm/s while saline was continuouslyinfused from the tip of the occlusion balloon. With afrequency-domain OCT system, a 2.7-F OCT imagingcatheter (Dragonfly JP, LightLab Imaging Inc.; orFastView, Terumo, Tokyo, Japan) was advanceddistal to the lesion and contrast media was injected ata flush rate of 3.0 to 4.0 ml/s through the guiding

FIGURE 2 A Representative Case With a CN in the Mid Right Coronary Artery

A CN was observed as a discrete round-shaped radiopacity (yellow arrow in D) in the mid right coronary artery. Diastole (A) and systole (B)

that have been magnified (C, diastole; D, systole). A hinge motion was seen at the site of the CN. The D angle was analyzed as the difference

of angle of systole (s) and diastole (d). (E) OCT images corresponding to the radiopacity in the angiogram. There was an accumulation of

nodular calcifications (small calcium deposits, white asterisks) with an overlaying white thrombus (white arrows). At the bottom of the CN

there was a thick calcified plate (white arrowheads). Abbreviations as in Figure 1.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 8 , 2 0 1 7 Lee et al.A U G U S T 2 0 1 7 : 8 8 3 – 9 1 Calcified Nodule Assessed by OCT

885

catheter; pullback was started as soon as the bloodwas cleared. All OCT images were analyzed usingproprietary software (St. Jude Medical Inc. or Ter-umo) by 2 experienced investigators using previouslyvalidated criteria for OCT plaque characterization(10–13). Calcium was defined as a signal-poor or het-erogeneous region with a sharply delineated border,and CN was defined as an accumulation of nodularcalcification (small calcium deposits) with disruptionof fibrous cap on the calcified plate (Figure 2E).Quantitative calcium analysis was performed every 1mm throughout the lesion. The maximum arc oftarget lesion calcium was measured in degrees with aprotractor centered on the lumen, and mean calciumarc was calculated as the sum of the calcium arcsdivided by calcium length. Maximum calcium thick-ness and fibrous cap thickness on the top of calciumwere analyzed at the maximum calcium arc site

adjacent to CN and at the maximum calcium arc sitein the lesions without CN. Lipidic plaque was definedas a low-signal region with a diffuse border, and anarc of lipid >90� was considered lipid-rich plaque.Thin-cap fibroatheroma was defined as a lipid-richplaque with a fibrous cap thickness <70 mm (14).Plaque rupture, thrombus, macrophage accumula-tions, and microchannels were also identified, asdescribed previously (12–14).

STATISTICAL ANALYSIS. Data analysis was per-formed using SPSS 22.0 (IBM, Armonk, New York).Categorical data were expressed as frequencies andcompared using the chi-square test or Fisher exacttest, as appropriate. The normality of the data wasverified using the Kolmogorov-Smirnov test. Becausemost values were not normally distributed, contin-uous variables were expressed as median values (first

TABLE 1 Patient Characteristics

All Lesions(N ¼ 889)

Lesions With CalcifiedNodule (n ¼ 37)

Lesions Without CalcifiedNodule (n ¼ 852) p Value

Age, yrs 66.1 (59.0, 74.0) 73.0 (65.0, 79.0) 66.0 (58.0, 73.0) 0.001

Female 20.0 (178) 40.5 (15) 19.1 (163) 0.001

Clinical presentation

Acute coronary syndromes 48.1 (428) 45.9 (17) 48.2 (411) 0.79

STEMI 19.0 (169) 10.8 (4) 19.4 (165) 0.28

Non-STEMI 21.5 (191) 27.0 (10) 21.2 (181) 0.40

Unstable angina 7.6 (68) 8.1 (3) 7.6 (65) 0.76

Stable angina 51.9 (461) 54.1 (20) 51.8 (441) 0.79

Diabetes mellitus 34.0 (302) 51.4 (19) 33.3 (283) 0.02

Hypertension 67.9 (604) 67.6 (25) 68.0 (579) 0.95

Dyslipidemia 55.3 (492) 45.9 (17) 55.8 (475) 0.24

Current smoker 39.0 (347) 25.0 (9) 39.7 (338) 0.08

Renal insufficiency* 28.3 (252) 27.8 (14) 27.9 (238) 0.19

Hemodialysis 3.3 (29) 18.9 (7) 2.6 (22) <0.001

Previous myocardial infarction 15.9 (141) 22.2 (8) 15.6 (133) 0.35

Previous PCI 24.2 (215) 27.0 (10) 24.1 (205) 0.69

Previous CABG 2.2 (20) 10.8 (4) 1.9 (16) 0.008

Thrombus aspiration 20.2 (154) 9.4 (3) 20.7 (151) 0.17

Values are % (n) or median (first quartile, third quartile). *Estimated glomerular filtration <60 ml/min/1.73 m2.

CABG ¼ coronary artery bypass grafting; PCI ¼ percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardial infarction.

TABLE 2 Angiographic Findings

All Lesions(N ¼ 889)

Lesions With CalcifiedNodule (n ¼ 37)

Lesions Without CalcifiedNodule (n ¼ 852) p Value

Lesion location

RCA ostium 0.4 (4) 8.1 (3) 0.1 (1) <0.001

RCA proximal 7.5 (67) 5.4 (2) 7.6 (65) 0.99

RCA mid 14.2 (126) 32.4 (12) 13.4 (114) 0.001

RCA distal 10.6 (94) 2.7 (1) 10.9 (93) 0.17

RCA branch 1.9 (17) 0.0 (0) 2.0 (17) 0.99

Left main 0.9 (8) 0.0 (0) 0.9 (8) 0.99

LAD ostium 2.1 (19) 5.4 (2) 2.0 (17) 0.19

LAD proximal 17.1 (152) 18.9 (7) 17.0 (145) 0.82

LAD mid 27.4 (244) 21.6 (8) 27.7 (236) 0.57

LAD distal 0.7 (6) 0.0 (0) 0.7 (6) 0.99

LAD branch 0.2 (2) 0.0 (0) 0.2 (2) 0.99

LCX ostium 0.7 (6) 0.0 (0) 0.7 (6) 0.99

LCX proximal 3.5 (31) 0.0 (0) 3.5 (31) 0.64

LCX mid 8.3 (74) 2.7 (1) 8.6 (73) 0.36

LCX branch 4.4 (39) 2.7 (1) 4.5 (38) 0.99

Pre–minimum lumen diameter, mm 0.88 (0.62, 1.22) 0.95 (0.77, 1.23) 0.87 (0.62, 1.21) 0.28

Pre–reference vessel diameter, mm 2.80 (2.45, 3.19) 2.73 (2.25, 3.22) 2.80 (2.46, 3.19) 0.33

Pre–diameter stenosis 66.9 (56.4, 77.0) 61.3 (56.4, 74.8) 67.2 (56.4, 77.3) 0.16

Lesion length, mm 13.3 (10.6, 17.8) 14.5 (10.7, 20.2) 13.3 (10.6, 17.7) 0.47

Any calcification 35.7 (317) 100.0 (37) 32.9 (280) <0.001

Moderate 24.5 (218) 27.0 (10) 24.4 (208) 0.72

Severe 11.1 (99) 73.0 (27) 8.5 (72) <0.001

Tortuosity 4.8 (43) 5.4 (2) 4.8 (41) 0.70

D Angle in culprit lesion, � 10 (6, 14) 16 (14, 21) 9 (6, 14) <0.001

Values are % (n) or median (first quartile, third quartile).

LAD ¼ left anterior descending coronary artery; LCX ¼ left circumflex artery; RCA ¼ right coronary artery.

Lee et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 8 , 2 0 1 7

Calcified Nodule Assessed by OCT A U G U S T 2 0 1 7 : 8 8 3 – 9 1

886

TABLE 3 Optical Coherence Tomography Findings

All Lesions(N ¼ 889)

Lesions With CalcifiedNodule (n ¼ 37)

Lesions Without CalcifiedNodule (n ¼ 852) p Value

Minimum lumen area, mm2 0.99 (0.67, 1.50) 1.20 (0.85, 1.74) 0.97 (0.66, 1.49) 0.056

Maximum calcium arc, � 69 (0, 135) 301 (247, 347) 64 (0, 123) <0.001

0 38.4 (341) 0 (0.0) 40.0 (341) <0.001

1–90 22.2 (197) 2.7 (1) 23.0 (196)

91–180 22.6 (201) 2.7 (1) 23.5 (200)

181–270 8.8 (78) 32.4 (12) 7.7 (66)

271–360 8.1 (72) 62.2 (23) 5.8 (49)

Mean calcium arc, � 51 (0, 85) 166 (134, 202) 48 (0, 81) <0.001

Calcium length, mm 2 (0, 7) 17 (15, 27) 2 (0, 6) <0.001

Maximum lipid arc, � 207 (143, 266) 0 (0, 141) 212 (148, 270) <0.001

Maximum calcium thickness, mm 0.35 (0, 0.81) 1.18 (0.94, 1.3) 0.21 (0, 0.75) <0.001

Fibrous cap thickness on top of calcium, mm 80 (50, 150) 37 (29, 58) 90 (50, 150) <0.001

Lipid-rich plaque* 83.7 (744) 35.1 (13) 85.8 (731) <0.001

Thin-cap fibroatheroma 32.6 (290) 5.4 (2) 33.8 (288) <0.001

Plaque rupture 32.3 (287) 13.5 (5) 33.1 (282) 0.01

Thrombus 39.1 (348) 48.6 (18) 38.7 (330) 0.23

Microchannel 347 (39.0) 29.7 (11) 39.4 (336) 0.24

Macrophage accumulations 45.4 (404) 29.7 (11) 46.1 (393) 0.05

Values are median (first quartile, third quartile) or % (n). *Maximum lipid arc >90� .

FIGURE 3 The Distribution of Calcified Nodules in the Coronary Arteries

Prevalence of Lesion Distribution in Total (n = 889)and Lesions with CN (n = 37)

40%

30%

20%

10%

0%

Ost

ium

LM LAD

5.4%

0%

Pro

xim

al

18.9%

Mid

21.6%

Dis

tal

0%

Bra

nch

0%

Ost

ium

RCA

8.1%

Pro

xim

al

5.4%2.7%

Mid

32.4%

Dis

tal

Bra

nch

0%

Ost

ium

LCX

0% 0%

Pro

xim

al

Mid

2.7% 2.7%

Bra

nch

Total (n = 889) CN (n = 37)

Distribution of all 889 lesions (pink color) and the prevalence of a calcified nodule (yellow color). Calcified nodules were more frequently

observed at the ostium or mid right coronary artery and proximal or mid left anterior descending coronary artery. LAD ¼ left anterior

descending coronary artery; LCX ¼ left circumflex artery; LM ¼ left main coronary artery; RCA ¼ right coronary artery; other abbreviation

as in Figure 1.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 8 , 2 0 1 7 Lee et al.A U G U S T 2 0 1 7 : 8 8 3 – 9 1 Calcified Nodule Assessed by OCT

887

FIGURE 4 Prevalence of Calcified Nodules in Relation to the Maximum Calcium Arc

Prevalence of Calcified Nodules in All LesionsA

0°

(N)

0.0%(0/341)

1 - 90°

0.5%(1/197)

91 - 180°

0.5%(1/201)

181 - 270°

15.4%(12/78)

271 - 360°

31.9%(23/72)

400

300

200

100

0

All lesions (n = 889)

Lesions with calcified nodules (n = 37)

Prevalence of Calcified Nodules in ACS LesionsB

0°

(N)

0.0%(0/195)

1 - 90°

0.0%(0/99)

91 - 180°

0.0%(0/77)

181 - 270°

22.2%(8/36)

271 - 360°

42.9%(9/21)

400

300

200

100

0

All ACS lesions (n = 428)

Calcified nodule lesions in ACS (n = 17)

(A) In the entire cohort of 889 lesions, 95% of calcified nodules were observed in the

presence of a maximum calcium arc >180�. (B) When only acute coronary syndromes

lesions were included, 42.9% of lesions with maximum calcium arc >270� had a calcified

nodule. ACS ¼ acute coronary syndromes.

TABLE 4 Comparison

Syndromes Versus St

Angiographic findings

RCA ostium location

RCA mid location

Lesion length, mm

D Angle in culprit les

Optical coherence tom

Minimum lumen area

Thrombus

Maximum calcium ar

Mean calcium arc, �

Calcium length, mm

Maximum lipid arc, �

Thin-cap fibroathero

Plaque rupture

Values are % (n) or median

Abbreviation as in Table

Lee et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 8 , 2 0 1 7

Calcified Nodule Assessed by OCT A U G U S T 2 0 1 7 : 8 8 3 – 9 1

888

quartile, third quartile) and were compared usingMann-Whitney U test. Intervariability and intra-variability were tested using Kappa stat for the diag-nosis of CN (categorical variable) and intraclasscorrelation coefficient for D angle (continuous

of Patients With a Calcified Nodule Presenting With Acute Coronary

able Angina

Calcified Nodule

p ValueAcute Coronary

Syndromes (n ¼ 17)Stable Angina

(n ¼ 20)

17.6 (3) 0.0 (0) 0.09

29.4 (5) 35.0 (7) 1.00

14.5 (10.6, 18.0) 14.6 (10.7, 20.8) 0.48

ion, � 16 (14, 20) 16 (14, 21) 0.90

ography findings

1.04 (0.69, 1.26) 1.61 (1.03, 2.06) 0.02

82.4 (14) 20.0 (4) <0.001

c, � 273 (233, 332) 304 (252, 347) 0.50

166 (123, 191) 167 (141, 211) 0.66

17 (14, 26) 18 (15, 27) 0.94

80 (0, 153) 0 (0, 103) 0.12

ma 5.9 (1) 5.0 (1) 0.99

17.6 (3) 0.0 (0) 0.09

(first quartile, third quartile).

2.

variable) using 40 randomly selected cases. Interob-server variability was assessed by 2 independent ob-servers for CN (Y.C. and A.M.) and D angle (M.M. andT.L.). Intraobserver variability was assessed by rean-alysis of a single observer 4 weeks later. The relation-ship between CN and clinical and anatomiccharacteristics was assessed using a multivariable lo-gistic regression model (with a stepwise forward se-lection) based on the results in Tables 1 to 3 along withknown clinical risk factors. Receiver operating char-acteristic analysis was used to determine the discrim-inatory capability as an area under the curve and theoptimal cutoff value using Youden index: themaximum value of (sensitivity þ specificity-1) for D

angle and maximum calcium arc to associate with thepresence of a CN. A p value <0.05 was consideredstatistically significant.

RESULTS

There was a good concordance of interobserver andintraobserver agreement for the diagnosis of CN(k ¼ 0.84, 0.90) and angiographic D angle (intraclasscorrelation coefficient ¼ 0.84, 0.92), respectively.

PREVALENCE OF CN. Overall, 4.2% of the 889 denovo culprit lesions contained a CN, and the preva-lence of CN was more frequent in the ostium or midright coronary artery (RCA) (Figure 3). Among 37 culpritlesions with a CN, almost all (35 lesions; 94.6%) wereobserved in the 150 culprit lesions that had amaximumcalcium arc >180� (Figure 4). When we included onlypatients with ACS, CN was the underlying culpritlesion morphology in 4.0% overall: in 29.8% of pa-tients with maximum calcium arc of >180� and in42.9% of patients with maximum calcium arc of>270�.

CLINICAL, ANGIOGRAPHIC, AND OCT CHARACTERISTICS.

Patients with a CN were older and more often female,and had a higher prevalence of diabetes mellitus,prior coronary bypass graft surgery, and hemodialysisversus those without a CN (Table 1). In the angio-graphic analysis, lesions containing a CN showedmore severe calcification and a greater D angle be-tween diastole and systole compared with thosewithout a CN (Table 2).

Culprit lesions containing a CN had a larger calciumarc (maximum and mean), longer calcium length,thicker calcium, and more superficial location of cal-cium compared with those without a CN (Table 3). Incontrast, culprit lesions with a CN had less lipid-richplaque and fewer thin-cap fibroatheromas and plaqueruptures compared with those without a CN (Table 3).

CLINICALANDANATOMICCHARACTERISTICSASSOCIATED

TO THE PRESENCE OF CN. Hemodialysis (odds ratio

TABLE 5 OCT Studies Describing Calcified Nodule

First Author (Ref. #) Study PopulationPopulationNumber

Prevalenceof CN, % OCT Findings Associated Findings to CN

Jia (18) ACS (STEMI 54, NSTE-ACS 50, others 22) 126 7.9 Higher prevalence of calciumor fibrous plaque comparedwith the lesions with plaquerupture or erosion

Older age, renaldysfunctionSTEMI 54 0

NSTE-ACS 50 10.0

Higuma (19) STEMI 111 8.0 Large calcium arc, shallowcalcium depth

Older age, negativeremodeling by IVUS

Kajander (20) STEMI 70 7.1 Not described Not described

Wang (21) STEMI 64 3.1 Not described Not described

ACS ¼ acute coronary syndrome; CN ¼ calcified nodule; IVUS ¼ intravascular ultrasound; NSTE-ACS ¼ non–ST-segment elevation acute coronary syndrome; OCT ¼ opticalcoherence tomography; STEMI ¼ ST-segment elevation myocardial infarction.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 8 , 2 0 1 7 Lee et al.A U G U S T 2 0 1 7 : 8 8 3 – 9 1 Calcified Nodule Assessed by OCT

889

[OR]: 4.0; 95% confidence interval [CI]: 1.1 to 13.4;p ¼ 0.04), angiographic D angle (OR: 1.09; 95% CI: 1.05to 1.14; p < 0.001), and maximum calcium arc (OR:1.02; 95% CI: 1.01 to 1.02; p < 0.001) were significantlyassociated with the presence of a CN in the multi-variable model. Receiver operating curve analysisfor predicting a CN indicated that maximum calciumarc had an area under the curve of 0.93 (p < 0.001),and D angle had an area under the curve of 0.80(p < 0.001). The optimal cutoff value of maximumcalciumarc andD anglewere 186� and 13�, respectively.

ASSOCIATION BETWEEN CN AND ACS PRESENTATION.

Although anatomic characteristics (ostial or mid-RCAlocation, greater in-lesion angiography D angle be-tween systole and diastole, and presence of severeangiographic calcification) associated with a CN in theoverall cohort were similar in patients presentingwith ACS, a smaller minimum lumen area accompa-nied by more thrombus was observed in the CN le-sions in patients presenting with ACS versus stableangina (Table 4). In the adjusted model the presenceof a CN (OR: 4.4; 95% CI: 1.9 to 10.1; p < 0.001) wasassociated with ACS presentation with a similar OR ofplaque rupture (OR: 4.6; 95% CI: 3.1 to 6.7; p < 0.001).

PROCEDURAL RESULTS. There were 685 patients(77.1%) who underwent post–percutaneous coronaryintervention OCT imaging. Post–percutaneous coro-nary intervention minimum stent area was notsignificantly different between the lesions with CNversus thosewithout (CN 7.08mm2 [first quartile, thirdquartile: 5.71, 8.78] vs. non-CN 6.76mm2 [first quartile,third quartile: 5.03, 8.16]; p ¼ 0.16) and in lesions withan arc of calcium >180� (CN 6.55 mm2 [first quartile,third quartile: 4.76, 7.99] vs. CN non-6.88 mm2 [firstquartile, third quartile: 5.46, 8.20]; p ¼ 0.32).

DISCUSSION

The major findings of our investigation are as follows:1) a CN was observed in 4.2% of all culprit lesions

irrespective of clinical presentation; 2) a CN was morefrequently located in ostial or mid-RCA lesions; 3)hemodialysis, larger D angle in culprit lesion betweendiastole and systole, and a larger OCT maximum cal-cium arc were associated with the presence of a CNirrespective of clinical presentation; and 4) in lesionswith severe calcification (maximum calcium arc>180�), 30% of ACS culprit lesions contained a CN,and the presence of a CN was associated with ACSpresentation independent of other vulnerable plaquemorphologies or other anatomic predictors of a CN inthe overall cohort.

In the first clinical report of a CN, 3 patients withACS had intracoronary angiographic filling defectsthat were initially diagnosed as intraluminal thrombi,but pre-intervention IVUS imaging showed thesefilling defects to be CNs, similar in appearance tothose in the present study (15). On histology, a CN hadthe greatest amount of calcification relative to plaquearea among vulnerable plaque subtypes and wasthought to be associated with a healed fibroatheromaand, potentially, intraplaque hemorrhage (16).

The prevalence of a culprit lesion CN has variedfrom 2% to 8% in previous reports (1,17–22). Virmaniet al. (1) reported a CN in 2.4% of patients with suddencardiac death. Using pathology as the gold standard,Lee et al. (17) reported a CN in 6.0% of cross-sectionswith IVUS calcification. Using OCT, Jia et al. (18) re-ported a 10% prevalence of CN culprit lesions in 50non–ST-segment elevation ACS patients and 0% in 54STEMI patients. In other OCT reports including onlySTEMI patients, the prevalence of CN in culprit lesionsvaried from 3.1% to 8.0% (19–21). The associationbetween CN and older age, renal dysfunction, and thepresence of calcification were consistent amongdifferent reports as shown in Table 5. In a previoussubanalysis from the 3-vessel PROSPECT imaging thatused IVUS–virtual histology to assess nonculpritlesions, the prevalence of nonculprit CN was reportedas 17% per artery (3). PROSPECT substudy also

PERSPECTIVES

COMPETENCY IN PATIENT CARE AND

PROCEDURAL SKILLS: CN were seen in 4.2% of all

lesions and were located more frequently in the ostial or

mid right coronary artery. Hemodialysis, coronary hinge

motion assessed by the in-lesion angiographic D angle

(between systole anddiastole), andmaximumcalciumarc

by optical coherence tomography were significantly

associatedwith the presence of CN. In lesionswith severe

calcification (maximumcalciumarc>180�), 30%of acute

ACS culprit lesions contained a CN, and the presence of a

CNwas associated with ACS presentation independent of

other vulnerable plaque morphologies.

TRANSLATIONAL OUTLOOK: Further multicenter,

prospective studies are needed to show the association

between a CN and clinical findings because of the small

population numbers in this study. The results of our study

suggest that the interventional strategymay bemodified

when culprit lesions show severe calcification in not only

stableanginabutalsopatientswithACS.Suchstudiesmay

establish clinical usefulness of intracoronary imaging,

especially in patients with severe calcification.

Lee et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 8 , 2 0 1 7

Calcified Nodule Assessed by OCT A U G U S T 2 0 1 7 : 8 8 3 – 9 1

890

reported that dense calcium volume was significantlygreater in lesions with a CN than in lesions without aCN (3), similar to other reports.

Previous pathological studies indicated that a CNwas associated with breaks in the calcified sheet, pre-dominantly in the mid-RCA where coronary torsionstress was maximum (1,22,23). Mechanical factors,such as a coronary hingemotion, especially in the RCA,might break the calcium sheet (6,19,24), which hasbeen seen with stent fracture as reported in previousstudies (25–27). Thus it is possible that a culprit lesionwith a CN might also be a marker for stent fracture.

In the present study hemodialysis was indepen-dently associated with the presence of a CN. Therelationship between renal dysfunction and coronarycalcification has been well known (28,29); however, itwas unclear whether there was additive impact ofhemodialysis on coronary instability in lesions withsevere calcification. One previous study of patientswith angiographic calcium reported that clinical5-year event rates in patients with hemodialysis werehigher than those without hemodialysis (30).

CN was more frequently seen in women than in menin the present study. When comparing clinical, angio-graphic, and OCT findings between men and women,women were older and had more renal insufficiencyand coronary artery calcium (data not shown).However, in multivariable analysis using the presenceof a culprit CN as the endpoint, female sex was nolonger significant after adjusting for the maximumcalcium arc. Therefore, it seemed as if the reason whywomen had more culprit CN was because women hadmore calcification due to older age and more renalinsufficiency and other cofounding factors.

In the present study the anatomic features of theCN were similar whether the patients presented withstable or unstable symptoms; the differentiating fea-tures were that CNs with ACS presentation had asmaller minimum lumen area accompanied by morethrombus compared with CNs with stable angina.Similarly, Fujii et al. (31) compared plaque ruptureswith versus without ACS presentation and showedthat clinical instability was associated with a smallerlumen area and/or thrombus formation. These 2studies suggest that the underlying morphology maybe less important than the impact on lumen narrow-ing leading to luminal thrombosis.

The present study showed that CN achieved asimilar final stent area compared with a lesionwithout CN. Previous OCT studies reported thatthe presence of calcium crack or fracture post-intervention was associated with better stent expan-sion (32,33). Lesions with a CN having a brokencalcium sheet could facilitate the stent expansion.

STUDY LIMITATIONS. First, this was a retrospectiveobservational study at a single center. Second, weexcluded lesions in which we anticipated difficulty inadvancing the OCT catheter. Third, the presence ofthrombus overlying the culprit lesion might havereduced the ability to assess the underlying plaquecharacteristics by OCT in some patients, and therequirement for thrombus aspiration before OCT mayhave affected the OCT findings; however, in patientswith ACS, thrombus aspiration was performed lessoften in lesions with a CN compared with thosewithout a CN (18% vs. 36%; p ¼ 0.19).

CONCLUSIONS

The presence of a CN was associated with severecalcification and larger hinge movement of coronaryartery (especially in the ostial or mid-RCA). One-thirdof underlying plaque morphology of ACS in severelycalcified culprit lesions was caused by CN, whichshould be taken into account during primary percu-taneous coronary intervention.

ADDRESS FOR CORRESPONDENCE: Dr. AkikoMaehara, Cardiovascular Research Foundation, 1700Broadway, 9th Floor, New York, New York 10019.E-mail: amaehara@crf.org.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 8 , 2 0 1 7 Lee et al.A U G U S T 2 0 1 7 : 8 8 3 – 9 1 Calcified Nodule Assessed by OCT

891

RE F E RENCE S

1. Virmani R, Kolodgie FD, Burke AP, Farb A,Schwartz SM. Lessons from sudden coronarydeath: a comprehensive morphological classifica-tion scheme for atherosclerotic lesions. Arte-rioscler Thromb Vasc Biol 2000;20:1262–75.

2. Virmani R, Burke AP, Farb A, Kolodgie FD.Pathology of the vulnerable plaque. J Am CollCardiol 2006;47:C13–8.

3. Xu Y, Mintz GS, Tam A, et al. Prevalence, dis-tribution, predictors, and outcomes of patientswith calcified nodules in native coronary arteries: a3-vessel intravascular ultrasound analysis fromProviding Regional Observations to Study Pre-dictors of Events in the Coronary Tree (PROS-PECT). Circulation 2012;126:537–45.

4. Jang IK, Bouma BE, Kang DH, et al. Visualiza-tion of coronary atherosclerotic plaques in pa-tients using optical coherence tomography:comparison with intravascular ultrasound. J AmColl Cardiol 2002;39:604–9.

5. Kubo T, Imanishi T, Takarada S, et al. Assess-ment of culprit lesion morphology in acutemyocardial infarction. J Am Coll Cardiol 2007;50:933–9.

6. Kume T, Akasaka T, Kawamoto T, et al.Assessment of coronary arterial plaque by opticalcoherence tomography. Am J Cardiol 2006;97:1172–5.

7. Saita T, Fujii K, Hao H, et al. Histopathologicalvalidation of optical frequency domain imaging toquantify various types of coronary calcifications.Eur Heart J Cardiovasc Imaging 2017;18:342–9.

8. Ino Y, Toyoda Y, Tanaka A, et al. Predictors andprognosis of stent fracture after sirolimus-elutingstent implantation. Circ J 2009:2036–41.

9. Mintz GS, Popma JJ, Pichard AD, et al. Patternsof calcification in coronary artery disease. A sta-tistical analysis of intravascular ultrasound andcoronary angiography in 1155 lesions. Circulation1995;91:1959–65.

10. Jang IK, Tearney GJ, MacNeill B, et al. In vivocharacterization of coronary atherosclerotic pla-que by use of optical coherence tomography.Circulation 2005;111:1551–5.

11. Yabushita H, Bouma BE, Houser SL, et al.Characterization of human atherosclerosis by op-tical coherence tomography. Circulation 2002;106:1640–5.

12. Prati F, Regar E, Mintz GS, et al. Expert reviewdocument on methodology, terminology, andclinical applications of optical coherence tomog-raphy: physical principles, methodology of imageacquisition, and clinical application for assessmentof coronary arteries and atherosclerosis. Eur HeartJ 2010;31:401–15.

13. Tearney GJ, Regar E, Akasaka T, et al.Consensus standards for acquisition, measure-ment, and reporting of intravascular opticalcoherence tomography studies: a report from theinternational working group for intravascular op-tical coherence tomography standardization andvalidation. J Am Coll Cardiol 2012;59:1058–72.

14. Lee T, Yonetsu T, Koura K, et al. Impact ofcoronary plaque morphology assessed by opticalcoherence tomography on cardiac troponinelevation in patients with elective stent implan-tation. Circ Cardiovasc Interv 2011;4:378–86.

15. Duissaillant GR, Mintz GS, Pichard AD, et al.Intravascular ultrasound identification of calcifiedintraluminal lesions misdiagnosed as thrombi bycoronary angiography. Am Heart J 1996;132:687–9.

16. Yahagi K, Kolodgie FD, Otsuka F, et al. Path-ophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat Rev Cardiol 2016;13:79–98.

17. Lee JB, Mintz GS, Lisauskas JB, et al. Histo-pathologic validation of the intravascular ultra-sound diagnosis calcified coronary artery nodules.Am J Cardiol 2011;108:1547–51.

18. Jia H, Abtahian F, Aguirre AD, et al. In vivodiagnosis of plaque erosion and calcified nodule inpatients with acute coronary syndrome by intra-vascular optical coherence tomography. J Am CollCardiol 2013;62:1748–58.

19. Higuma T, Soeda T, Abe N, et al. A combinedoptical coherence tomography and intravascularultrasound study on plaque rupture, plaqueerosion, and calcified nodule in patients with ST-segment elevation myocardial infarction: inci-dence, morphologic characteristics, and outcomesafter percutaneous coronary intervention. J AmColl Cardiol Intv 2015;8:1166–76.

20. Kajander OA, Pinilla-Echeverri N, Jolly SS,et al. Culprit plaque morphology in STEMI—anoptical coherence tomography study: insightsfrom the TOTAL-OCT substudy. EuroIntervention2016;12:716–23.

21. Wang L, Parodi G, Maehara A, et al. Variableunderlying morphology of culprit plaques associ-ated with ST-elevation myocardial infarction: anoptical coherence tomography analysis from theSMART trial. Eur Heart J Cardiovasc Imaging 2015;16:1381–9.

22. Sakakura K, Nakano M, Otsuka F, Ladich E,Kolodgie FD, Virmani R. Pathophysiology ofatherosclerosis plaque progression. Heart LungCirc 2013;22. 399–41.

23. Otsuka F, Joner M, Prati F, Virmani R, Narula J.Clinical classification of plaque morphology incoronary disease. Nat Rev Cardiol 2014;11:379–89.

24. Mori H, Finn AV, Atkinson JB, Lutter C,Narula J, Virmani R. Calcified nodule: an early andlate cause of in-stent failure. J Am Coll Cardiol Intv2016;9:e125–6.

25. Omar A, Pendyala LK, Ormiston JA,Waksman R. Review: stent fracture in the drug-eluting stent era. Cardiovasc Revasc Med 2016;17:404–11.

26. Kuramitsu S, Iwabuchi M, Haraguchi T, et al.Incidence and clinical impact of stent fracture af-ter everolimus-eluting stent implantation. CircCardiovasc Interv 2012;5:663–71.

27. Kuramitsu S, Iwabuchi M, Yokoi H, et al. Inci-dence and clinical impact of stent fracture afterthe Nobori biolimus-eluting stent implantation.J Am Heart Assoc 2014;3:e000703.

28. Sarnak MJ, Levey AS, Schoolwerth AC, et al.Kidney disease as a risk factor for developmentof cardiovascular disease: a statement from theAmerican Heart Association Councils on Kidneyin Cardiovascular Disease, High Blood PressureResearch, Clinical Cardiology, and Epidemi-ology and Prevention. Circulation 2003;108:2154–69.

29. Sugiyama T, Kimura S, Ohtani H, et al.Impact of chronic kidney disease stages onatherosclerotic plaque components on opticalcoherence tomography in patients with coronaryartery disease. Cardiovasc Interv Ther 2016;32:216–24.

30. Nishida K, Kimura T, Kawai K, et al. Compari-son of outcomes using the sirolimus-eluting stentin calcified versus non-calcified native coronarylesions in patients on- versus not on-chronic he-modialysis (from the j-Cypher registry). Am JCardiol 2013;112:647–55.

31. Fujii K, Kobayashi Y, Mintz GS, et al. Intra-vascular ultrasound assessment of ulceratedruptured plaques: a comparison of culprit andnonculprit lesions of patients with acute coro-nary syndromes and lesions in patients withoutacute coronary syndromes. Circulation 2003;108:2473–8.

32. Maejima N, Hibi K, Saka K, et al. Relationshipbetween thickness of calcium on opticalcoherence tomography and crack formationafter balloon dilatation in calcified plaquerequiring rotational atherectomy. Circ J 2016;80:1413–9.

33. Kubo T, Shimamura K, Ino Y, et al. Superficialcalcium fracture after PCI as assessed by OCT.J Am Coll Cardiol Img 2015;8:1228–9.

KEY WORDS calcium, imaging, opticalcoherence tomography, plaque