Author + information
- Received August 2, 2016
- Revision received October 7, 2016
- Accepted November 10, 2016
- Published online October 2, 2017.
- Yaping Zeng, MD, PhDa,b,
- Hiroki Tateishi, MD, PhDa,
- Rafael Cavalcante, MD, PhDa,
- Erhan Tenekecioglu, MDa,
- Pannipa Suwannasom, MDa,c,
- Yohei Sotomi, MDc,
- Carlos Collet, MDc,
- Shaoping Nie, MD, PhDb,
- Hans Jonker, BScd,
- Jouke Dijkstra, MD, PhDe,
- Maria D. Radu, MD, PhDa,f,
- Lorenz Räber, MD, PhDa,g,
- Dougal R. McClean, MDh,
- Robert-Jan van Geuns, MD, PhDa,
- Evald H. Christiansen, MD, PhDi,
- Therese Fahrni, RNj,
- Jacques Koolen, MD, PhDk,
- Yoshinobu Onuma, MD, PhDa,
- Nico Bruining, PhDa and
- Patrick W. Serruys, MD, PhDl,∗ ()
- aThoraxCentre, Erasmus Medical Center, Rotterdam, the Netherlands
- bThe Emergency & Critical Care Center of Beijing Anzhen Hospital, Capital Medical University, Beijing, the People’s Republic of China
- cAcademic Medical Center, Amsterdam, the Netherlands
- dCardialysis BV, Rotterdam, the Netherlands
- eDivision of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
- fDepartment of Cardiology, Rigshospitalet, Copenhagen, Denmark
- gDepartment of Cardiology, Bern University Hospital, Bern, Switzerland
- hDepartment of Cardiology, Christchurch Hospital, Christchurch, New Zealand
- iDepartment of Cardiology, Aarhus University Hospital, Skejby Hospital, Aarhus, Denmark
- jDepartment of Cardiology, Swiss Cardiovascular Center, University Hospital, Bern, Switzerland
- kCardiology, Catharina Ziekenhuis, Eindhoven, the Netherlands
- lInternational Centre for Circulatory Health, Imperial College, London, United Kingdom
- ↵∗Address for correspondence:
Prof. Dr. Patrick W. Serruys, Westblaak 98, 3012KM, Rotterdam, the Netherlands.
Objectives The aim of this study was to assess calcium growth with fused grayscale intravascular ultrasound (IVUS), IVUS–virtual histology, and optical coherence tomography (OCT) from baseline to 5-year follow-up in patients treated with bioresorbable vascular scaffolds.
Background IVUS and OCT have individual strengths in assessing plaque composition and volume. Fusion of images obtained using these methods could potentially aid in coronary plaque assessment.
Methods Anatomic landmarks and endoluminal radiopaque markers were used to fuse OCT and IVUS images and match baseline and follow-up.
Results Seventy-two IVUS–virtual histology and OCT paired matched cross-sectional in- and out-scaffold segments were fused at baseline and follow-up. In total, 46 calcified plaques at follow-up were detected using the fusion method (33 in-scaffold, 13 out-scaffold), showing either calcium progression (52.2%) or de novo calcifications (47.8%). On OCT, calcification volume increased from baseline to follow-up by 2.3 ± 2.4 mm3 (p = 0.001). The baseline virtual histologic tissue precursors of dense calcium at follow-up were necrotic core in 73.9% and fibrous or fibrofatty plaque in 10.9%. In 15.2%, calcium was already present at baseline. Precursors on OCT were lipid pool in 71.2%, fibrous plaque in 4.3%, and fibrocalcific plaque in 23.9%.
Conclusions The use of OCT and IVUS fusion imaging shows similar calcium growth in- and out-scaffold segments. Necrotic core is the most frequent precursor of calcification. The scaffold resorption process creates a tissue layer that re-caps the calcified plaques. (Absorb Clinical Investigation, Cohort B [ABSORB B]; NCT00856856)
Coronary atherosclerotic plaque characterization with intravascular imaging is important for assessing atherosclerosis, planning percutaneous coronary interventions, and predicting outcomes (1). Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) are the 2 most widely used intracoronary imaging techniques.
The main advantage of IVUS lies in its deep penetration ability, which offers a cross section of the entire vessel wall and allows the detection of deep calcification. Its main disadvantages are limited resolution and the strong reflection of the ultrasound waves by endoluminal calcium, which creates a shadow behind the calcium that precludes assessment of the extent and depth of calcification (2).
IVUS–virtual histology (VH) increases the usefulness of IVUS by characterizing tissue components and allowing better risk stratification (1). However, stent and scaffold struts are incorrectly recognized as dense calcium (DC) surrounded by necrotic core (NC) on VH. Moreover, the VH algorithm also incorrectly inputs fibrofatty signal in the shadow behind DC (3,4).
OCT enables a detailed assessment of near-lumen plaque characteristics because of its high resolution (10 to 20 μm), including features related to plaque vulnerability such as thin fibrous caps. OCT can also assess calcifications more accurately because the light can cross calcified areas without being excessively reflected and without substantial attenuation, allowing visualization of the real extent of calcification plaque along its longitudinal and axial distribution, at least in the relatively superficial layer of the vessel wall (5). However, the high resolution comes at the cost of limited depth of penetration (6). Therefore, OCT is unable to detect deep calcium.
The feasibility and advantages of combining the individual strengths of both technologies in vivo have been described (7). The feasibility of off-line fusion images of coregistered IVUS and OCT has been previously described (8).
The objective of the present study was to comprehensively assess the serial progression of calcification at 5-year follow-up after bioresorbable vascular scaffold (BVS) implantation using matched fusion images from IVUS and OCT. We sought to evaluate calcium progression and describe the baseline tissue precursors of calcification at long-term follow-up.
In Cohorts B1 and B2 from ABSORB (Absorb Clinical Investigation) (n = 101), 28 patients with 29 lesions underwent IVUS and OCT assessment at baseline and 5 years (9) (Online Figure 1). OCT, grayscale (GS)–IVUS, and IVUS-VH images were displayed simultaneously and screened concomitantly frame by frame to match using radiopaque markers and/or anatomic marks at each time point (Online Figure 2). Then the matched cross sections selected were colocalized between 2 time points. Each cross section was subdivided into 4 quadrants, and the presence of each type of atherosclerotic plaque was assessed in each quadrant (7).
Post-implantation and 5-year images were obtained using 20-MHz, phased-array IVUS catheters (Eagle Eye, Volcano, Rancho Cordova, California) using an automated pull-back of 0.5 mm/s. Semiautomatic detection of both lumen and external elastic membrane was performed using QCU-CMS-Research software version 4.69 (Medis Medical Imaging, Leiden, the Netherlands). Calcification on GS-IVUS was defined as bright echoes with acoustic shadowing (2).
IVUS radiofrequency analysis
On IVUS-VH analysis, “pseudo” DC or NC related to the scaffold strut was defined as confluent, uninterrupted white color surrounded by red color, located near the lumen contour. DC located behind the struts and separated from the struts was considered as real DC at baseline (10). The “white color” was then defined as calcification if the confluent white-color area exceeded 0.0625 mm2 (0.25 × 0.25 mm), considering the resolution of the 20-MHz IVUS catheters used in the study (2). To determine the major baseline tissue precursor of calcifications at 5 years, fusion images weighting VH information in topographically matched calcified areas at follow-up were used. The baseline VH tissue precursor was determined as the major tissue component, if it constituted approximately 50% of the total tissue.
OCT image acquisition and analysis
OCT acquisition was performed using C7/C8 frequency domain systems (Light Lab Imaging, Westford, Massachusetts) (11). The OCT images acquired at baseline and follow-up were analyzed off-line at 100- or 200-μm longitudinal intervals within the region of interest (ROI) using QCU-CMS.
Three tissue components were identified on the basis of consensus of 5 analysts: fibrous, fibrocalcific, and lipid pool (lipid or NC) (11) (Online Appendix). The baseline OCT tissue precursor of calcifications at follow-up was defined as the tissue component constituting approximately 50% in topographically matched calcified area.
Matching cross section and ROI definition
The matching of multimodalities at 1 time point and at follow-up is performed according to the following criteria: the presence of platinum marker (BVS) and common anatomic landmarks such as side branch, vein, pericardium, position and configuration of calcified plaque, characteristic lumen shape and circumferential profile of plaque thickness, and/or positional or directional relationship among all these landmarks (Figure 1). The following cross section is not included in the analysis (Online Appendix). The ROI was defined as the scaffold segment and 5 mm proximal and distal.
Fusion cross section of IVUS and OCT
The principles of fusion imaging have been previously described (8). In summary, the matched GS-IVUS, IVUS-VH, and OCT images were adjusted and fused in Adobe Photoshop Elements 12 (Adobe Systems, San Jose, California) (Figure 1). Detailed processes were as follows.
First, the sizes of OCT and IVUS images were adjusted by matching the 1-mm calibration line. The original square shape of both IVUS and OCT images was well defined, so that matching of the 1-mm calibration line between OCT and IVUS images was maintained, thus allowing matching of square image areas.
Second, the 2-dimensional cross-sectional images were rotated using cross-sectional landmarks according to the following hierarchy: 1) side branch; 2) calcification; 3) lumen shape; and 4) circumferential plaques.
Third, to optimize the overlay of IVUS on top of OCT images, the transparency function of Photoshop Elements was used to allow simultaneous visibility of the structures in the underlying OCT images. As a suitable default setting for overlaying IVUS on top of OCT images, transparency of 60% to 70% for the grayscale IVUS images and 70% to 80% for IVUS-VH images was applied.
Calcium assessment by fusion IVUS and OCT
To assess the diagnostic accuracy of calcium detection of each individual modality compared with the fusion images, the cross sections of each modality were evaluated by 3 teams of 2 cardiologists who were blind to the images of the other modalities at baseline and 5 years using the criteria described earlier.
After having assessed individually the presence or absence of calcification in each imaging modality, a group of 5 cardiologists assessed by consensus the diagnosis of calcification in the matched cross section. Calcification was diagnosed by fusion when qualitative and quantitative criteria were met by at least 2 imaging modalities. Sensitivity and specificity of each modality were determined using the fusion image as comparator.
OCT and IVUS calcification measurements
The following OCT parameters were assessed (Figure 2): calcium area, volume, arc, axial and longitudinal length, and intima thickness overlying calcifications (12); calcium volume was calculated on the basis of the disk summation method (Online Appendix).
Automatic quantitative echogenicity analysis
Echogenicity classifies plaque components into 5 categories on the basis of their gray-level intensity on IVUS: calcified, upper-echogenic, hyperechogenic, hypoechogenic, and unknown (13).
Continuous variables are presented as mean ± SD or as median and interquartile range (IQR) as appropriate and were compared using the paired Student t test or Wilcoxon signed rank test for baseline versus follow-up comparisons and the independent Student t test and Mann-Whitney U test for in- versus out-scaffold. Binary variables are summarized as counts and percentages and were compared using the chi-square or Fisher exact test. For each imaging modality alone, sensitivity and specificity for calcium detection were determined using the fusion method as the comparator. Agreement for calcium detection between each modality and the fusion method was assessed using the Cohen κ statistic. Because the data in the study had multilevel structure, a mixed-effects model was used. Patients were implemented as the random effect, and in- or out-scaffold segment was input as the fixed effect. A 2-sided p value <0.05 indicated statistical significance. All analyses were performed using SPSS version 22 (IBM, Armonk, New York).
Study population and case selection
Among 28 patients with complete 5-year follow-up in the ABSORB Cohort B trial, 15 (16 lesions) with all 3 imaging modalities (GS-IVUS, IVUS-VH, and OCT) available were included in the present analysis. Baseline clinical characteristics of the study population are summarized in Table 1, and IVUS measurements at baseline and 5 years are shown in Table 2. Patients imaged with time-domain OCT were excluded from the analysis (Online Figure 1).
In the 16 coronary lesions, at baseline, 72 cross sections (4.6 ± 1.4 cross sections per lesion) of each of the 3 imaging modalities (IVUS, IVUS-VH, and OCT) were matched and fused using the criteria stated earlier. These fused cross sections were further matched with the corresponding 72 fused cross sections from the 5-year follow-up assessment. These constituted the study database of 72 pairs of matched, fused (GS-IVUS, IVUS-VH, and OCT) cross sections.
No calcification was observed in 33 of these 72 pairs of cross sections (41.8%) (i.e., at neither time point). In the other 39 pairs of fused cross sections (58.2%), 46 calcified area pools were detected at 5-year follow-up. These 46 calcified area pools represented either calcium progression from baseline (n = 24) or de novo calcification (n = 22) (Figure 3).
Of note, calcium was detected by VH only at baseline in 22 cross sections. To definitively determine the true significance of this isolated VH signal, follow-up fusion images were assessed, and calcification was confirmed in 13 of 22 cross sections. In the remaining 9 cross sections, the VH signal of calcification either disappeared or persisted only as an isolated VH signal not confirmed by the fusion method.
Diagnostic accuracy of calcification with fusion and individual modalities
Table 3 shows the sensitivity and specificity of each modality in detecting calcium at 2 time points, using the fusion modality as the comparator.
Analysis of tissue precursor of calcification on OCT and IVUS-VH
On IVUS-VH, the tissue precursors of DC at baseline were NC (n = 34 [73.9%]) and fibrous or fibrofatty plaque (n = 5 [10.9%]). In the remaining 7 calcifications (15.2%), calcium was already present at baseline. On OCT, precursors were lipid pool (n = 33 [71.2%]), fibrous plaque (n = 2 [4.3%]), and fibrocalcific tissue (n = 11 [23.9%]).
OCT calcium measurements
An overall increase in calcium area was observed both in-scaffold (Δ = 0.37 mm2; IQR: 0.25 to 0.74 mm2) and out-scaffold (Δ = 0.39 mm2; IQR: 0.21 to 1.2 mm2) (p = 0.098, in- vs. out-scaffold). The mixed-effects model showed a similar trend (p = 0.117).
Serial changes in intima thickness overlying the calcified plaque as well as axial calcium length and arc were analyzable in 14 plaques (9 in- and 5 out-scaffold) at both time points. Minimal intima thickness overlying calcium increased significantly more for in-scaffold (Δ = 180 ± 152 μm) than out-scaffold (Δ = 16 ± 116 μm) segments (p = 0.034, in- vs. out-scaffold), although it was statistically nonsignificant (p = 0.079) after mixed-effects analysis. Overall, the mean intima thickness, maximal intima thickness, axial calcium length, and arc significantly increased at follow-up, with no differences between in- and out-scaffold segments before and after using the mixed-effects model (Table 4).
Longitudinal calcium length (1.8 ± 0.71 mm at baseline vs. 3.6 ± 2.0 mm at 5 years; p = 0.003) and volume (0.83 ± 0.64 mm3 at baseline vs. 3.1 ± 2.5 mm3 at 5 years; p = 0.001) significantly increased at follow-up.
IVUS calcification arc measurements
GS-IVUS detected calcium at both time points in 21 plaques. An overall increase in calcium arc was observed, with no difference between in-scaffold (Δ = 16 ± 13°) and out-scaffold (Δ = 35 ± 28°) segments (p = 0.134, in- vs. out-scaffold), and a similar trend was observed after mixed-effects analysis (p = 0.075) (Table 4).
Calcium assessment with IVUS echogenicity
IVUS echogenicity was evaluated in 39 cross sections containing 46 calcified area pools. An increase in calcium area was observed, with no difference between in-scaffold (Δ = 0.21 mm2; IQR: 0.1 to 0.28 mm2) and out-scaffold (Δ = 0.22 mm2; IQR: 0.03 0.37 mm2) segments (p = 0.881, in- vs. out-scaffold); after applying the mixed-effects model, p = 0.887 (Online Table 1).
The findings of the present study can be summarized as follows: 1) fusion OCT and IVUS images provide a comprehensive assessment of coronary artery calcification; 2) calcification progresses to a similar extent in in-scaffold and out-scaffold segments, suggesting that calcification is a global phenomenon not influenced by the presence of the scaffold; 3) the intima thickness overlying calcium in-scaffold is thicker than out-scaffold segments and may constitute a new endoluminal lining isolating the calcified plaque from the lumen; 4) IVUS-VH has high sensitivity for the detection of calcification; and 5) lipid pool and NC are the most frequent precursors of calcifications at follow-up.
Calcification detection with fusion of OCT and IVUS
Coronary artery calcium affects the pathophysiologic development of atherosclerosis and triggers cardiac events. In addition, its severity and endoluminal topography affect interventional strategy and clinical events (14). In the present study, calcification was evaluated by fusion of OCT, GS-IVUS, and IVUS-VH, which improved the diagnostic accuracy of calcification by combining the individual strengths of each modality. As for the diagnostic accuracy of individual modalities in detecting calcification, GS-IVUS at baseline showed lower sensitivity than IVUS-VH, which could be explained by the fact that the complex classification tree and algorithm for tissue analysis on IVUS-VH relies on backscattering of the radiofrequency signal, whereas GS-IVUS detects only the envelope of the ultrasonic signal.
In this analysis, the specificity of OCT was high, but the sensitivity was limited. Among possible reasons for the low sensitivity are the limited penetration of OCT, which precludes the detection of deep calcium deposits, guidewire artifacts, and tangential signal dropout.
IVUS-VH, however, showed 100% sensitivity and low specificity for calcium detection. Some isolated, localized IVUS-VH DC signals at baseline were considered artifacts when not confirmed by grayscale and/or OCT calcium detection. Interestingly, some of these isolated VH signals (13 of 22) became fully calcified plaques at follow-up in the same topographic area detected using the fusion method (Figure 4). This unexpected finding might reopen the debate on the diagnostic value of IVUS-VH for the detection of calcium (15,16). The validation study with IVUS-VH obtained from 45-MHz rotation IVUS has demonstrated the capacity of the VH algorithm to detect microcalcification in ROIs as small as 0.25 × 0.25 mm (3).
Calcified plaque development and precursors
In the present study, calcifications (calcium area, arc, axial length, calcified echogenicity) were shown to increase to a similar extent in both in- and out-scaffold segments. This implies a global calcification phenomenon unrelated to the implantation of the scaffold. Calcium progression has been shown in patients on secondary prevention and statin treatment (17). This natural history is thought to reflect a plaque-stabilizing phenomenon associated with lipid-lowering therapy (18).
Previous data have shown indirectly that at follow-up, atherosclerosis regresses by decreasing its NC content and increasing its DC content on average (17–19). Our study is the first to date to clearly and directly demonstrate that phenomenon at the plaque and cross section level. Only by this meticulous paired, matched analysis of in vivo data with long-term follow-up were we able to demonstrate the transformation of NC into calcium, as the vast majority of tissue precursors were NC or lipid pool. The molecular mechanisms for this transformation remain largely unclear, but “mineral deposit,” “osteoprotegerin,” and efferocytosis of macrophage are the possible mechanisms (20,21). Coregistration of multislice computed tomography and fluoride-18 positron emission tomography has clearly demonstrated dynamic and inflammatory changes in calcified lesions. Fluoride is taken up by macrophages, liposomes, and microcalcification. In addition, NC on IVUS-VH has been colocalized with calcification visualized by multislice computed tomography and fluoride-18 positron emission tomography (22).
Regulatory bodies in Europe and the United States have raised concerns over bioresorption of fully bioresorbable scaffold in polylactide: local acidification and transient detection (Von Kossa staining) of calcification around the degraded scaffold strut have been reported in preclinical models as early as 28 days but had disappeared at long-term follow-up (23). Despite these reassuring preclinical data, clinicians remain concerned by the long-term outcomes of polylactide bioresorbable scaffolds. For instance, in preclinical studies, it has been demonstrated that metallic bioresorbable scaffolds in magnesium evolve into soft amorphous hydroxyapatite of calcium (24).
The progression and development of new calcified plaque should not be confused with neoatherosclerosis, whose OCT features are very specific (25). It must be emphasized that the luminal area in the present series was 6.4 mm2 at baseline and 6.3 mm2 at 5 years, with no sign of restenosis or luminal encroachment (Table 2).
Re-capping of the calcified plaque
Despite the appearance and progression of calcifications, the new lesions could be considered stable for the following reasons: at 5-year follow-up, a moderately thick layer of neointima (272 ± 149 μm) is located on top of each calcified plaque in-scaffold segment (Figures 4D and 4F′). The minimal intima thickness overlying the calcification increased significantly more in in-scaffold segments at 5-year follow-up compared with out-scaffold segments. The term “re-capping of the plaque” has been coined to describe this phenomenon (12).
This “cap” overlying the calcification is likely due to the integration of the polymeric struts into the vessel wall, which isolates the lumen from the underlying calcium and the surrounding lipid and NC. The “cap” may transform the unstable phenotype of plaque to a stable one by covering the calcific spots and thin-cap fibroatheroma with neointima (12); furthermore, calcium with a homogenous thick cap will have less effect on the shear stress than spotty superficial calcium (26).
This study represents the longest natural history of evolution of plaques analyzed serially by fusion IVUS and OCT. There were nevertheless some methodological limitations. First, precise and careful matching of images acquired with a sampling rate as different as 1 frame/s from VH to 100 or 180 frames/s for OCT considerably reduces the number of analyzable cross sections per lesion. The goal of the study was not to unravel clinical implications but to generate hypotheses. Therefore caution should be exercised when extrapolating the study results given the limited number of cross sections.
Second, the lack of intracoronary images pre-procedure renders the analysis of true tissue composition more complex, because strut artifacts are detected as “pseudo” DC and NC on IVUS-VH images. To account for that, we excluded struts from the IVUS images according to a previously validated method (10).
Third, we did not use any automated imaging software specifically validated to create fused images. Therefore, the display of the presented images is purely exploratory but may serve as a preamble for further development of dedicated software application on imaging on the basis of photoacoustic systems (27), as well as hybrid technique (28).
Fourth, the data on lipid profiles and medications in this study were collected as general clinical information. It was clearly stipulated in the protocol that the investigators had to follow the guidelines of the European Society of Cardiology (at the time of the trial design, target low-density lipoprotein <2 mmol/l). In the present study at 5 years, 14 of 15 patients were treated with hydroxymethylglutaryl coenzyme-A reductase inhibitors (3 with rosuvastatin, 7 with atorvastatin, and 5 with simvastatin). Low-density lipoprotein was well controlled and decreased from baseline (2.6 ± 0.5 mmol/l) to 5 years (1.6 ± 0.5 mmol/l). All 15 patients presented with at least 1 calcification in the selected 72 fused cross sections. The limited number of observations does not allow any physiopathological or pharmacological interpretation.
Fifth, our findings are limited to segments treated with BVS and cannot be extrapolated to segments treated with metallic stents or untreated ones. Of note, because the struts get resorbed at about 2 years of follow-up, we can speculate that at 5 years, the behavior of the vascular wall should be close to that of an untreated segment.
Finally, because no validation against histologic findings was performed, our results should be cautiously interpreted as hypothesis generating regarding the potential benefits of hybrid imaging techniques.
With the use of OCT and IVUS fusion imaging, we demonstrate in vivo similar calcium growth in in-scaffold and out-scaffold segments in patients treated with BVS. NC is the most frequent precursor of calcification. The scaffold resorption process creates a tissue layer that re-caps calcified plaques.
COMPETENCY IN MEDICAL KNOWLEDGE: Both OCT and IVUS alone have limitations in evaluating calcification. In this study, by fusing OCT and IVUS, we have shown that similar calcium growth in in-scaffold and out-scaffold segments in patients treated with BVS. NC is the most frequent precursor of calcification.
TRANSLATIONAL OUTLOOK: In the future, coregistration of OCT and IVUS techniques (e.g., acquisition with hybrid catheters) will likely be in clinical practice. Future research is needed to define whether calcification is a sign of plaque progression or stabilization of coronary atherosclerosis. Remaining questions include ascertaining the molecular mechanism and determining how to use pharmacological intervention targeting calcification to stabilize the plaque.
The authors thank H.M. Garcia-Garcia for his work in the core laboratory for many years, including the analysis used in the present work.
Drs. Räber, Onuma, and Serruys are members of the advisory board of Abbott Vascular. Dr. Zeng was sponsored by Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Zeng and Tateishi contributed equally to this work.
- Abbreviations and Acronyms
- bioresorbable vascular scaffold
- dense calcium
- interquartile range
- intravascular ultrasound
- necrotic core
- optical coherence tomography
- region of interest
- virtual histology
- Received August 2, 2016.
- Revision received October 7, 2016.
- Accepted November 10, 2016.
- 2017 American College of Cardiology Foundation
- Mintz G.S.,
- Nissen S.E.,
- Anderson W.D.,
- et al.
- Kubo T.,
- Imanishi T.,
- Takarada S.,
- et al.
- Gonzalo N.,
- Garcia-Garcia H.M.,
- Regar E.,
- et al.
- Serruys P.W.,
- Ormiston J.,
- van Geuns R.J.,
- et al.
- Tearney G.J.,
- Regar E.,
- Akasaka T.,
- et al.
- Bourantas C.V.,
- Serruys P.W.,
- Nakatani S.,
- et al.
- Mintz G.S.
- Stone G.W.,
- Mintz G.S.
- Thim T.,
- Hagensen M.K.,
- Wallace-Bradley D.,
- et al.
- Nasu K.,
- Tsuchikane E.,
- Katoh O.,
- et al.
- Banach M.,
- Serban C.,
- Sahebkar A.,
- et al.
- Otsuka F.,
- Sakakura K.,
- Yahagi K.,
- Joner M.,
- Virmani R.
- Doris M.K.,
- Newby D.E.
- Onuma Y.,
- Serruys P.W.,
- Perkins L.E.,
- et al.
- Vengrenyuk Y.,
- Carlier S.,
- Xanthos S.,
- et al.
- Kim J.,
- Lee D.,
- Jung U.,
- Kim C.
- Bourantas C.V.,
- Jaffer F.A.,
- Gijsen F.J.,
- et al.