Evaluation of the thickness of coronary calcium by 60-MHz intravascular ultrasound: head-to-head comparison with optical frequency domain imaging

The region behind the coronary calcium could not be visualized by intravascular ultrasound (IVUS) because of acoustic shadow. However, some pathological studies have shown that IVUS delineated the vessel border behind thin coronary calcium sheets. This study aimed to reveal whether recent IVUS can visualize the region behind thin coronary calcium sheets. Using 534 cross-sectional optical frequency domain images (OFDI), including severe calcified coronary lesions, calcium sheet thickness was measured by every 1°. Accordingly, the visibility of the vessel border behind the coronary calcium sheet was evaluated using 60-MHz IVUS images, which were longitudinally linked with OFDI ones. After carefully coordinating with the axial position, the association between the IVUS-derived permeability of the coronary calcium sheet and calcium thickness was evaluated. The maximum and mean calcium thickness by OFDI was 0.88 ± 0.39 and 0.62 ± 0.30 mm, respectively. By 60-MHz IVUS, 12.1% of the coronary calcium sheets had permeable segments. Comparing between OFDI and IVUS images, 48.6% of the coronary calcium sheets with maximum thickness ≤ 0.3 mm were sometimes permeable by 60-MHz IVUS, whereas most > 0.5 mm thick calcium sheets were impermeable. In the receiver operating characteristic curve analysis, the best cutoff values for the maximum and mean thickness of permeable calcium were 0.48 and 0.31 mm, respectively. Thus, 60-MHz IVUS can occasionally visualize the region behind a thin coronary calcium sheet. When using 60-MHz IVUS, this finding may be a predictive marker of calcium sheet with a thickness of < 0.5 mm.


Introduction
Despite the use of second-generation drug-eluting stents for patients undergoing percutaneous coronary intervention (PCI), coronary calcification, especially angiographically Intravascular ultrasound (IVUS), which is more commonly used in daily practice for assessing lesion morphologies than OCT and OFDI [8, 9], could not evaluate calcium plaque thickness because of acoustic shadows in the region behind the calcium sheet [6,10].Physician using IVUS for coronary calcium evaluation, might wish that it can evaluate calcium thickness similar to OCT.However, on a comparison study between pathological findings and IVUS images, 20-40 MHz IVUS delineated the vessel border behind the thin calcium sheet [11][12][13].Based on these findings, we hypothesized that the recent 60-MHz IVUS system could visualize the region behind the thin coronary calcium sheet without an acoustic shadow.To verify our hypothesis, we aimed to perform a head-to-head comparison between OFDI and IVUS findings of coronary calcium.

Study population and intravascular image acquisition
Between March 2019 and October 2020, a total of 1019 patients who underwent PCI at Iwate Medical University Hospital or Nakadori General Hospital were consecutively enrolled in our PCI registry.Of them, 48 patients with chronic coronary syndrome had angiographically severe calcified lesions and underwent orbital or rotational atherectomy under intravascular imaging.Finally, 11 lesions in 11 patients who underwent both 60-MHz IVUS and OFDI before procedures were registered for the present study.For image acquisition, either the Lunawave® OFDI System with the FastView® Imaging Catheter (Terumo Corporation, Tokyo, Japan) or the Visicube® 60-MHz IVUS System with the AltaView® Imaging Catheter (Terumo Corporation) was used in this study.OFDI and IVUS images were obtained at a rate of 158 frames/s with a 40 mm/s pullback speed (4 images/mm) and 90 images/s with a 9 mm/s pullback speed (10 images/mm), respectively.This observational study complied with the Declaration of Helsinki and was approved by the ethics committees at each participating institution (MH2019-125).

OFDI and IVUS image analysis
Two independent reviewers (Y.O. and M.I.) analyzed OFDI images using a dedicated workstation (LUNAWAVE Offline Viewer, Terumo, Tokyo, Japan), and compared both

D)
Using these images, the visibility of the vessel border behind the calcium sheet was qualitatively evaluated.A double-headed dotted arrow shows an invisible vessel border.IVUS, intravascular ultrasound; OFDI, optical frequency domain imaging intravascular images using OsiriX (Pixmeo, Geneva, Switzerland).For the qualitative assessment of OFDI images such as calcium thickness and angles, we applied previously published methods [14].To coordinate with the longitudinal and axial positions, we performed the following steps: (1) every 1-mm cross-sectional OFDI image was divided into quarter (90-degree) segments (Fig. 1A).(2) Calcium thickness was measured every 1° using pre-installed software, which was designed for the measurement of neointima thickness (Fig. 1B).(3) All cross-sectional IVUS images were longitudinally and axially linked to the OFDI crosssectional images using landmarks such as branches and calcium appearance (Fig. 1C).(4) The visibility of the vessel border behind the calcium sheet was qualitatively evaluated in every 90° segmental IVUS images and compared with the maximum or mean calcium thickness in the linked OFDI images (Fig. 1D).Regarding the visibility assessment of calcium, a segment with a clearly visible vessel border behind the calcium sheet was defined as "permeable" (Fig. 2).On the contrary, the case with an unclear or invisible vessel border behind the calcium sheet was defined as "impermeable."In the case of ambiguous findings, the final diagnosis was determined by consensus of two reviewers.When IVUS detected OFDI-undetectable calcium and OFDI detected IVUS-undetectable calcium, we excluded these images from comparison between the two imaging modalities.

Post-stent OFDI and IVUS image analysis
To evaluate the subsequent response of the permeable calcium to stenting, findings between pre-procedure and poststent images by both OFDI and IVUS were compared, and whether calcium fracture occurred at the site of permeable segment was evaluated.Because less than 180° calcium rarely experience fracture after stenting [15], only largeangle (> 180-degree) calcium sheets having permeable segments were assessed.

Statistical analysis
Continuous values are presented as the mean ± standard deviation and categorical variables as a number or frequency.Cohen's κ was calculated for the intra-and interobserver variabilities of the identification of the visibility of the vessel border behind the calcium sheet.A receiver operating characteristic (ROC) curve analysis was performed to thick coronary calcium sheet in the upper right part (*) had acoustic shadow behind it (impermeable calcium).On the contrary, a thin coronary calcium sheet in the lower left part ( †) had no acoustic shadows.Therefore, the vessel border behind a thin calcium sheet could be visualized by IVUS (permeable calcium).IVUS, intravascular ultrasound; OFDI, optical frequency domain imaging calcified lesions.Of these lesions, 9 (82%) were diagnosed as AHA/ACC type B2/C lesion.In this study, orbital atherectomy was used for 4 patients, while rotational atherectomy was used for 7 patients (Table 2).

Evaluation of the calcium angle, length and thickness by OFDI
In 11 severe calcified lesions, the mean maximum calcium angle and % length of calcium was 312° ± 70° and 84.7% ± 12.4%, respectively.From 534 registered cross-sectional OFDI images, 2136 quartered segments were assessed for their maximum and mean calcium thickness.Excluding the segments without calcium (n = 984) and segments with immeasurable images because of backward attenuation or wire artifacts (n = 122), 1030 quartered segments with analyzable calcium sheets were finally evaluated for calcium thickness by every 1°.As a result, the maximum and mean calcium thickness values were 0.88 ± 0.39 and 0.62 ± 0.30 mm, respectively.

Assessment by IVUS and head-to-head comparison of IVUS and OFDI
When 534 OFDI-matched cross-sectional IVUS images were assessed, IVUS could visualize 12 OFDI-undetectable calcium, which were then excluded from the head-to-head comparison of IVUS and OFDI.Moreover, no IVUS-undetectable calcium was detected by OFDI.After excluding the images without coronary calcium (n = 134), we finally analyzed 388 cross-sectional images including coronary calcium that could be visualized by both imaging modalities.Of them, the frequencies of visible vessel border behind 0-90°, 91-180°, 181-270°, 271-360° coronary calcium were 10.7%, 16.2%, 10.2%, and 0%, respectively (Fig. 3).Focusing on the relationship between OFDI-derived calcium thickness and the visibility of the vessel border behind the calcium sheet by IVUS, coronary calcium sheets with > 0.5 mm of maximum and mean thickness were mostly diagnosed as impermeable by IVUS, whereas 48.6% of coronary calcium sheets with ≤ 0.3 mm of maximum thickness were permeable (Fig. 4).The ROC curve analysis demonstrated that the cutoff values for the maximum and mean thickness of the permeable calcium were 0.48 mm (sensitivity, 0.89; specificity, 0.93; area under the curve, 0.95) and 0.31 mm (sensitivity, 0.88; specificity, 0.89; area under the curve, 0.94), respectively (Fig. 5).In this study, the inter-and intra-observer κ coefficients for the visibility of the vessel border behind calcium sheets were 0.59 and 0.66, respectively.establish the cutoff thickness values of permeable calcium.All statistical analyses were performed using IBM SPSS Statistics version 27.0 (IBM Corp., Armonk, NY, USA).

Baseline patient and lesion characteristics
Baseline patient and angiographic characteristics are presented in Table 1.The mean age of the patients was 71.3 ± 9.0 years, and 8 (73%) patients were male.No patients were undergoing maintenance hemodialysis.Regarding angiographic findings, all lesions were diagnosed as severe maximum and mean calcium thickness values in the permeability of 60-MHz IVUS were 0.48 and 0.31 mm, respectively.(4) Among large-angle coronary calcium sheets, the permeable segments located in the middle of the calcium arc is rarely found but is associated with calcium fracture after stenting.These results suggest that coronary calcium sheets permeable by 60-MHz IVUS is most likely to be < 0.5 mm in thickness and could be a fracture point after stenting.
This study demonstrated that IVUS-derived thin coronary calcium sometimes lacks an acoustic shadow when assessed by 60-MHz IVUS.The possible main reason is that thin coronary calcium could be allowed 60-MHz ultrasound signals to pass through.A previous study in the urological field demonstrated that small-sized renal stone does not make an acoustic shadow when assessed by ultrasonography [16].Additionally, when rotator cuff calcific tendinopathy was evaluated using ultrasonography, nondense calcification appeared as a homogeneously hyperechoic region without an acoustic shadow, whereas dense calcification exhibited an acoustic shadow [17].Depending on the thinness and sparse density of the calcium sheet, IVUS could visualize the region behind the calcium sheet without an acoustic shadow.Another reason could be that a thin coronary calcium sheet does not have a necrotic core behind it, which makes strong signal attenuation during IVUS [18].According to a pathological report, a developed fibroatheroma involves not only the coronary calcium but a necrotic

Association of calcium fracture with "permeable" calcium
Focusing on large-angle (> 180°) calcium sheets, 17% of permeable segments were found in the middle of the constricted segments of calcium arc, whereas most of the permeable segments were found at the edge of the calcium arc.When permeable segments were compared between the pre-procedure and post-stent images, calcium fracture was found at the same portion of the permeable segment in some cases with a middle constricted segment (Fig. 6).However, the others, which had permeable segment at the edge of the calcium arc, had not experienced a calcium fracture after stenting.

Discussion
In this head-to-head comparison study of OFDI and 60-MHz IVUS, we sought to evaluate whether the thinness of coronary calcium sheets correlates with the visibility of the vessel border behind the calcium sheet assessed by 60-MHz IVUS.The main findings of this study are as follows: (1) IVUS sometimes can visualize the vessel border behind a thin coronary calcium sheet.(2) By contrast, thick sheets with > 0.5 mm and/or circumferential coronary calcium are never permeable by 60-MHz IVUS.(3) The cutoff for the In this study, the cutoff thickness value for the permeable calcium was slightly lower than 0.5 mm, which was associated with a risk of stent underexpansion [22].In other words, if the vessel border behind the calcium is visible by 60-MHz IVUS, the lesion would obtain good expansion after stent implantation.Therefore, 60-MHz IVUS-identified thin coronary calcium may be a predictor of stent expansion.On the contrary, > 180° calcium with thin (< 0.5 mm) segment in the middle, which is potentially breakable by stent implantation, is rare in the lesion targeted by PCI [14,23].Indeed, in this study, large-angle calcium sheets with permeable segments were observed only in 1.5% of calcified plaques.Our predictive finding is very attractive for PCI operators

Study limitations
This observational study has several limitations.First, the number of analyzed cases was small, although > 1000 OFDI-matched IVUS images were analyzed.Second, the cutoff value for permeable calcium may be different between Terumo IVUS and other 60-MHz IVUS, such as those made by Boston Scientific and ASCIT.Third, since coronary calcium was assessed by OFDI and 60-MHz IVUS, the diagnostic accuracy for assessing coronary calcium may be slightly different from pathological assessments.Fourth, because of subjective assessment, the reproducibility of permeable calcium may slightly vary according to experienced estimators.Further studies are needed to establish the clinical evidence for this finding.

Conclusion
The visibility of the vessel border behind the coronary calcium sheet by 60-MHz IVUS may be a predictive marker of calcium sheets with a thickness of < 0.5 mm.While they are rarely observed in the lesion targeted by PCI, this finding would be useful to predict stent expansion when assessing pre-PCI IVUS images.

Fig. 1
Fig. 1 Evaluation methods of coronary calcium and comparison of coronary calcium between OFDI and 60-MHz IVUS.A) Every 1-mm cross-sectional OFDI image was divided into 90° segments.B) Calcium thickness was measured for every 1°.C) 60-MHz IVUS images were longitudinally and axially linked to OFDI cross-sectional images.

Fig. 2
Fig. 2 Representative images of permeable and impermeable coronary calcium sheets by OFDI and 60-MHz IVUS.(A) OFDI image.(B) 60-MHz IVUS image corresponding to (A).OFDI showed coronary calcium sheets in both the upper right (*) and lower left ( †) parts.The maximum thickness values of both coronary calcium sheets were 0.64 and 0.32 mm, respectively.Focusing on the 60-MHz IVUS image, a

Fig. 3
Fig. 3 Frequency distribution of IVUS-derived permeability in 0-90, 91-180, 181-270, and 271-360° calcium.Black bar, impermeable calcium; white bar, permeable calcium core [19].Thus, early development of a coronary atheroma before the development of a necrotic core could allow the ultrasound signal to pass through the thin calcium sheet.All previous IVUS studies showing the permeability of coronary calcium were using 20-40 MHz IVUS [11-13].Although the ultrasound frequency in recent IVUS has increased up to 60-MHz to improve image resolution [6], no study has demonstrated that 60-MHz IVUS can visualize the vessel wall behind thin coronary calcium sheets.According to a previous study comparing 60-and 38-MHz IVUS system, the visualization of coronary calcium was similar in both IVUS images [20].However, 20-MHz IVUS can visualize the region behind a calcium sheet with less attenuation than 45-MHz IVUS, although 45-MHz IVUS has higher image resolution than 20-MHz [21].Therefore, 60-MHz IVUS may be able to transparent coronary calcium

Fig. 4
Fig. 4 Frequency distribution of permeable and impermeable coronary calcium sheets in each calcium thickness as assessed by OFDI.(A) Maximum calcium thickness, (B) mean calcium thickness.Black bar, impermeable calcium; white bar, permeable calcium.In this study, but has little practical value for predicting stent expansion because of low prevalence.

Fig. 5
Fig. 5 Receiver operating characteristic curves to determine the optimal cutoff value of the maximum or mean calcium thickness.(A) Maximum calcium thickness.(B) Mean calcium thickness

Fig. 6
Fig. 6 Representative case of a large-angle calcium sheet with a permeable segment.(A) Pre-PCI OFDI demonstrating coronary calcium sheets of approximately 270° with thin (dagger) and thick (asterisk) segments with a constricted segment (arrowheads).(B) By post-PCI OFDI assessment, a 270°coronary calcium sheet split into thin (dagger) and thick (asterisk) segments, which were caused by a calcium

Table 1
Baseline patient and angiographic characteristics American College of Cardiology, AHA = American Heart Association, eGFR = estimated glomerular filtration rate, LAD = left anterior descending artery, LCX = left circumflex artery, RCA = right coronary artery