Author + information
- Received January 22, 2019
- Revision received April 24, 2019
- Accepted June 11, 2019
- Published online December 21, 2019.
- Kenichiro Otsuka, MD, PhDa,
- Martin Villiger, PhDa,
- Antonios Karanasos, MD, PhDb,c,
- Laurens J.C. van Zandvoort, BScb,
- Pallavi Doradla, PhDa,
- Jian Ren, PhDa,
- Norman Lippok, PhDa,
- Joost Daemen, MD, PhDb,
- Roberto Diletti, MD, PhDb,
- Robert-Jan van Geuns, MD, PhDb,d,
- Felix Zijlstra, MD, PhDb,
- Gijs van Soest, PhDb,
- Jouke Dijkstra, PhDe,
- Seemantini K. Nadkarni, PhDa,
- Evelyn Regar, MD, PhDb,f and
- Brett E. Bouma, PhDa,b,g,∗ ()
- aWellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- bDepartment of Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, the Netherlands
- c1st Department of Cardiology, Hippokration Hospital, University of Athens, Athens, Greece
- dDepartment of Cardiology of Radboud UMC, Nijmegen, the Netherlands
- eDivision of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
- fHeart Center, University Hospital Zurich, Zurich, Switzerland
- gInstitute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts
- ↵∗Address for correspondence:
Dr. Brett E. Bouma, Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, 50 Blossom Street, Boston, Massachusetts 02114.
Objectives The aims of this first-in-human pilot study of intravascular polarimetry were to investigate polarization properties of coronary plaques in patients and to examine the relationship of these features with established structural characteristics available to conventional optical frequency domain imaging (OFDI) and with clinical presentation.
Background Polarization-sensitive OFDI measures birefringence and depolarization of tissue together with conventional cross-sectional optical frequency domain images of subsurface microstructure.
Methods Thirty patients undergoing polarization-sensitive OFDI (acute coronary syndrome, n = 12; stable angina pectoris, n = 18) participated in this study. Three hundred forty-two cross-sectional images evenly distributed along all imaged coronary arteries were classified into 1 of 7 plaque categories according to conventional OFDI. Polarization features averaged over the entire intimal area of each cross section were compared among plaque types and with structural parameters. Furthermore, the polarization properties in cross sections (n = 244) of the fibrous caps of acute coronary syndrome and stable angina pectoris culprit lesions were assessed and compared with structural features using a generalized linear model.
Results The median birefringence and depolarization showed statistically significant differences among plaque types (p < 0.001 for both, 1-way analysis of variance). Depolarization differed significantly among individual plaque types (p < 0.05), except between normal arteries and fibrous plaques and between fibrofatty and fibrocalcified plaques. Caps of acute coronary syndrome lesions and ruptured caps exhibited lower birefringence than caps of stable angina pectoris lesions (p < 0.01). In addition to clinical presentation, cap birefringence was also associated with macrophage accumulation as assessed using normalized standard deviation.
Conclusions Intravascular polarimetry provides quantitative metrics that help characterize coronary arterial tissues and may offer refined insight into coronary arterial atherosclerotic lesions in patients.
Plaque morphology and composition have been implicated in the pathogenesis of acute coronary syndromes (ACS) (1,2). The high resolution of optical coherence tomography (OCT) and optical frequency domain imaging (OFDI) has enabled the identification of several structural features of plaque instability (3–6). Despite much progress, prospective identification of rupture-prone plaques, which would be crucial to stratify risk and improve patient management, remains elusive (7–10). Current OCT and OFDI modalities rely on subjective interpretation and fall short of providing an objective and quantitative assessment of plaque morphology and composition (11–14).
Recently, we have introduced intravascular polarimetry by using polarization-sensitive (PS) OFDI in combination with standard intravascular OFDI catheters (15–17). Intravascular polarimetry complements the high-resolution imaging of subsurface microstructures known from OCT and OFDI with polarimetric measurements of tissue birefringence and depolarization (15,16). Tissue with fibrillar architecture, such as interstitial collagen or layered arrays of arterial smooth muscle cells, exhibits birefringence, which can serve to assess collagen and smooth muscle cell content (16,18). Depolarization corresponds to the randomization of the detected polarization states (19) caused by the propagation of light through tissue containing lipid particles, macrophage accumulation, or cholesterol crystals (16). In our previous study comparing intravascular polarimetry with histopathology, we showed that tissue birefringence and depolarization provide useful compositional information and offer advanced tissue characterization (16). The aim of the present study was to investigate, for the first time, the polarization properties of atherosclerotic plaques in patients with coronary artery disease. We explored how the quantitative polarization metrics evaluated in entire cross sections vary among different types of plaques, classified by conventional OFDI according to established qualitative structural criteria (plaque analysis). Moreover, we compared the polarization properties measured locally in the fibrous caps of culprit lesions between patients with ACS and stable angina pectoris (SAP) (cap analysis).
This first-in-human pilot study of intravascular polarimetry enrolled 30 nonconsecutive patients (ACS, n = 12; SAP, n = 18) undergoing percutaneous coronary intervention at Erasmus University Medical Center between December 2014 and July 2015. The ethics committee at Erasmus University Medical Center approved the protocol, and each patient gave written informed consent before inclusion in the study, which was conducted in compliance with the protocol and the Declaration of Helsinki. PS OFDI was performed using commercial intravascular catheters (FastView, Terumo, Tokyo, Japan) with a custom-built PS OFDI system (Supplemental Appendix), as previously described (15–17). Imaging in the 30 patients yielded a total of 36 pull backs, performed either before the procedure (n = 15; culprit or target vessel, n = 13; nonculprit or nontarget vessel, n = 2) or after the procedure (n = 21). Patient characteristics are summarized in Table 1.
The present study comprises a plaque analysis evaluating entire cross sections evenly distributed along all imaged coronary arteries and a cap analysis focusing solely on the fibrous caps of culprit lesions (Figure 1A). For the plaque analysis, all pull backs were uniformly divided into segments of 5 mm in length, progressing distally and proximally from the culprit lesion (Figure 1B). From the resulting total of 508 segments, comprising 2,540-mm pull back length, 166 segments were excluded from the analysis because of the following criteria: 1) containing a stent or from within 5 mm proximal or distal to an implanted stent (n = 150); 2) subject to pre-dilatation (n = 2); and 3) poor image quality due to insufficient blood clearing (n = 14). In each of the retained 342 5-mm segments, only the cross section with the smallest luminal area was identified for further analysis. If this cross section contained a side branch of diameter >1.5 mm, it was replaced with another section from the same segment. For segments containing fibroatheromas, instead of the smallest luminal area, the cross-section with the thinnest fibrous cap thickness was used for analysis.
For the cap analysis, we identified the culprit lesion in patients with ACS (n = 4) and SAP (n = 9) who underwent PS OFDI prior to percutaneous coronary intervention (Figure 1A). ACS culprit lesions were identified on the basis of invasive coronary angiography, electrocardiographic ST-segment alterations, and/or regional wall motion abnormality on echocardiographic assessment. SAP target lesions were determined on the basis of left ventricular wall motion abnormalities, nuclear scan, stress test, and coronary angiographic findings. For the cap analysis, we identified the cross section with the smallest luminal area in the culprit or target lesion of each patient (Figure 1B). Every other cross-sectional image up to 5 mm both proximally and distally, if featuring a lipid arc exceeding >90°, was included into the analysis, resulting in a total of 244 cross sections.
Conventional OFDI analysis
Two independent investigators (A.K. and L.J.C.Z.) analyzed the conventional OFDI appearance of the selected images using QCU-CMS viewing software (Leiden University Medical Center, Leiden, the Netherlands). Conventional OFDI analysis was performed blinded to the polarimetric signals. Luminal area was measured in all cross sections. Percentage area stenosis was calculated as previously reported (8), taking the mean of the largest lumen within 5 mm proximal and distal to the lesion containing the current cross section as the reference.
Each selected cross-section was then categorized as either of normal artery, fibrous plaque (FP), fibrofatty plaque (FF), fibrocalcified plaque (FC), thick-cap fibroatheroma (ThCFA), thin-cap fibroatheroma (TCFA), or plaque rupture (PR), on the basis of the conventional OFDI signal (Figures 2A1 to 2G1). Briefly, a vessel with a tunica intima thinner or similar in thickness to the tunica media was labeled as a normal artery (Figure 2A1). FP was defined as a plaque with high backscattering and relatively homogeneous OFDI signal (Figure 2B1). Plaques with calcium, which appears as a signal-poor or heterogeneous region with a sharply delineated border within fibrous tissue, were classified as FC (Figure 2D1) (9). A plaque with a lipid arc of more than 90° was defined as a fibroatheroma. A lipid-rich plaque with a lipid arc extending <90° was categorized as FF, to appreciate the optical properties of the small lipid-rich area (Figure 2C1). In fibroatheromas, the fibrous cap thickness was measured around its thinnest part 3 times by each observer, and then the averaged value was calculated. If the fibrous cap thickness was <65 μm, the plaque was categorized as TCFA and as ThCFA otherwise. PR was defined as a plaque featuring intimal disruption and cavity formation (Figures 2E1 to 2G1). In cases of discordance between the observers, a third investigator (B.E.B.) acted as referee to achieve consensus classification, and the majority was used as the final plaque classification.
Quantitative birefringence and depolarization analysis
PS OFDI analysis was performed at Massachusetts General Hospital blinded to the conventional OFDI measurements and clinical information. Coregistration between conventional OFDI and polarimetric signals is intrinsic, because they are computed from the exact same raw data. For the plaque analysis, we segmented the intimal layer of each cross section using custom-written software in MATLAB (The MathWorks, Natick, Massachusetts). In addition to the lumen, we segmented the internal elastic lamina, whenever visible, using the birefringence map to leverage from the improved visibility of the media in the birefringence map (16). In areas in which the internal elastic lamina segmentation was unattainable, typically in lipid-rich areas of advanced lesions, an automatic outer border corresponding to a tissue depth of 1 mm from the luminal surface was used. We also segmented calcifications and areas of thrombus. To compute the average birefringence of cross sections, we evaluated the median of the birefringence in the area bounded by the lumen and the internal elastic lamina or outer border segmentation, excluding the guidewire shadow, and featuring a depolarization of ≤0.2 as previously reported (17). The median depolarization was computed within the entire segmented area after masking the guidewire shadow.
For the cap analysis, the border between the fibrous caps of the culprit fibroatheromas and the underlying lipid or necrotic core was drawn manually, together with the lipid arc angle extending from the center of the lumen (total cap analysis). Mean and thinnest fibrous cap thickness were automatically calculated from the segmented fibrous cap in MATLAB. Furthermore, to investigate the features of fibrous caps at their thinnest part (focal cap analysis), we also defined a narrower arc angle, centered on the thinnest part of each cap (29° on average). In addition, we evaluated the normalized standard deviation (NSD) within the fibrous caps, which has been shown to correlate with macrophage infiltration (3,12). NSD was computed by first evaluating the standard deviation of the linear-scale backscatter intensity data within elliptical regions of interest, extending by 80 μm in depth and 12° in the circumferential direction and moved across the entire cap area. These values were then normalized with the difference between the maximum and the minimum intensity within each fibrous cap.
Continuous outcome measures are reported as mean ± SD. For the plaque analysis, the mean of the birefringence and of the logarithm of the depolarization values across the different plaque types were compared using 1-way analysis of variance. Pairwise comparison was performed using the Bonferroni correction if the overall test was significant. For comparison with clinical presentation in the cap analysis, the 1 PR lesion in the SAP group was classified together with the ACS lesions into an ACS and/or PR group. Differences in the means between the 2 groups were analyzed using a univariate generalized linear model using a generalized estimating equation to take into consideration the intrasubject correlations among multiple cross-sectional images from individual patients. The relationships between polarization properties and clinical and conventional OFDI parameters were determined using a univariate generalized linear model using a generalized estimating equation. Beta values and 95% confidence intervals for birefringence are given in units of ×10−3 throughout the paper. A p value of <0.05 was considered to indicate statistical significance, and all tests were 2 sided. SPSS version 22.0 was used for all analyses (IBM, Armonk, New York).
Polarization properties of individual plaque types
Table 1 summarizes patient characteristics and OFDI parameters for the overall study population. The selected 342 cross-sectional images representing all imaged vessels were classified into normal artery (n = 31), FP (n = 84), FF (n = 45), FC (n = 81), ThCFA (n = 88), TCFA (n = 11), and PR (n = 2) on the basis of conventional OFDI. Computing the weighted κ coefficient for multiple categories, excellent intra- and interobserver agreement was observed for the 7 plaque categories (κ = 0.98 and κ = 0.97, respectively). Figure 3 shows significant differences in median birefringence and depolarization among the 7 plaque types (p < 0.001 for both, 1-way analysis of variance). Comparing individual plaque types, normal arteries were significantly less birefringent than all other plaque types (p < 0.01), except for TCFA (p = 0.124) and PR (p = 1.00). FPs featured the highest birefringence, followed by FFs, FCs, ThCFAs, TCFAs, and PRs in decreasing order, but without statistical significance between individual categories (Figure 3A). Normal arteries also featured the lowest depolarization. PR showed the highest depolarization among the 7 plaque types. Except FF versus FC, ThCFA versus TCFA, ThCFA versus PR, and TCFA versus PR, all plaque types had statistically significant differences in depolarization when compared individually (Figure 3B).
Calcifications featured low birefringence and low depolarization (Supplemental Figures S1A and S1B). Calcifications located in fibrous tissue exhibited lower birefringence and depolarization than those in lipid-rich lesions (p < 0.001 for both), as shown in Supplemental Figures S1C and S1D. Thrombus (white thrombus) presented very low birefringence and depolarization (Supplemental Figures S2A and S2B).
Polarization properties of fibrous caps in culprit lesions
The lipid arc and minimum fibrous cap thickness differed with statistical significance between the ACS and/or PR and the SAP groups, as shown in Table 2. When comparing the polarimetric signals of the fibrous caps in the culprit lesions, we found lower birefringence in the ACS and/or PR group than in patients with SAP (p = 0.002), but comparable depolarization (p = 0.772) (Figures 4A and 4B).
Table 3 shows generalized estimating equation model parameters for the relationships among polarization properties, clinical presentation, and conventional OFDI parameters, when analyzing the entire cap. Birefringence of the total cap was negatively correlated with ACS and/or PR (β = −0.156; p = 0.002) and NSD (β = −0.021; p = 0.013). Depolarization of the total cap was negatively associated with mean fibrous cap thickness (β = −0.001; p < 0.001) and positively with lipid arc (β = 0.001; p = 0.001) and tended to be correlated with NSD (β = 0.005; p = 0.062). Furthermore, we analyzed narrow regions of interest centered on the thinnest part of each fibrous cap (Table 4). The generalized linear model using generalized estimating equation showed that ACS and/or PR (β = −0.138; p < 0.001), thinnest fibrous cap thickness (β = 0.005; p = 0.001), and NSD (β = −0.012; p = 0.001) were associated with birefringence. Factors associated with depolarization were thinnest fibrous cap thickness (β = −0.001; p = 0.005) and NSD (β = 0.004; p < 0.001).
This first-in-human pilot study of intravascular polarimetry demonstrates how it augments conventional OFDI plaque characterization with quantitative polarization properties, measured through standard intravascular OFDI catheters simultaneously with the conventional OFDI signal. The polarization features offer refined insight into tissue composition, consistent with our current understanding of the mechanisms involved in plaque progression and destabilization. The major finding of this study is that fibrous caps in ACS culprit lesions and ruptured plaques exhibit lower birefringence compared with the caps of target lesions in SAP patients within our limited study cohort. Compared with the interpretation of conventional OFDI, which relies on subjective identification of qualitative features, polarimetry offers quantitative metrics, leading the way toward objective and automated characterization of atherosclerotic plaques, which may facilitate the use of intravascular imaging in clinical practice. The improved assessment of plaque composition afforded by the polarization features may provide novel insight into the mechanism of plaque progression and instability in human coronary atherosclerosis (Central Illustration).
Polarimetric plaque characterization
Smooth muscle cells and collagen are known to influence the polarization of near infrared light (18). Our recent study of intravascular PS OFDI in cadaveric human hearts revealed that normal intimal tissue exhibits low birefringence compared with intimal tissue in fibrous, early, and advanced atherosclerotic lesions (16). In the present study, we observed significant differences in polarization properties, especially in depolarization, among all plaque types, despite analyzing the entire manually segmented intimal layer, comprising both the angle subtended by the plaque and the remainder of the cross section. Depolarization featured significant differences even among individual plaque types, whereas birefringence was less distinguishing. These observations suggest that PS OFDI provides insight into biological aspects of plaque progression and destabilization, complementary to the structural information available to conventional OFDI. Combined analysis of birefringence and depolarization in more refined automatically segmented regions of interest may offer automated tissue characterization. Moreover, accurate diagnosis of TCFA by OCT and OFDI remains challenging (13), and future studies are warranted to investigate the polarization features of thin and thick fibrous caps and early and late necrotic cores in detail.
Polarization properties in fibrous caps
Within our limited patient cohort, we observed that the fibrous cap of the culprit lesion in patients with ACS and/or PR exhibited significantly lower birefringence than in the caps of target lesions in those with SAP. Fibrillar collagen is the primary extracellular matrix molecule imparting both birefringence and mechanical stability to the fibrous cap overlying an atheroma (20). Histopathologic studies showed that ruptured fibrous caps lack layered smooth muscle cells and feature different collagen phenotypes than intact caps (20), which offers an explanation for the low birefringence observed in the fibrous caps of patients with ACS and/or PR. In addition to cap birefringence, minimum fibrous cap thickness and lipid arc angle also featured statistically significant differences between these 2 patient groups. Yet fibrous cap thickness alone is insufficient to identify caps that are prone to rupture (4,5,8,9). The polarization metrics available to intravascular polarimetry complement these structural features and may advance our understanding of the pathogenesis of ACS with or without fibrous cap rupture (10,21).
Furthermore, birefringence and depolarization of the fibrous cap were associated with increased NSD, suggesting macrophage accumulation. Inflammation is a known mechanism of plaque destabilization (2,22,23). Macrophages release enzymes including matrix metalloproteinases that destroy the extracellular matrix and weaken the cap (22). Our observations suggest that the presence of active macrophages may increase depolarization, whereas the effect of their presence causes a reduction in birefringence. The physical mechanism inducing depolarization in atherosclerosis remains to be elucidated. We speculate that lipid droplets exceeding the size of the wavelength used for OFDI and small cholesterol crystals, which have been postulated to be a crucial factor in the initiation of inflammatory response in atherosclerosis (24), are the origin of the observed depolarization.
Consistent with our previous cadaveric human heart study of intravascular polarimetry (16), we observed that calcifications located in fibrous tissue exhibited lower birefringence and depolarization than those in lipid-rich lesions. Although the OFDI appearance of microcalcifications has not been established (6), we speculate that their presence in fibrous caps contributes to a reduction of the cap birefringence, together with a lack of collagen organization and content and absence of smooth muscle cells. The few occurrences of white thrombus in the present study had minimal impact on the underlying polarization signatures. However, the stronger attenuation of red thrombus may lead to an apparent increase in depolarization that would impair interpretation of the underlying vessel wall, similar to conventional OFDI.
First, our study consisted of a small number of patients from a cohort of nonconsecutive patients and was cross-sectional in design. Considering potential selection bias of patients, our findings should be interpreted with caution, although we included all patients imaged with intravascular polarimetry. Furthermore, the limited number may have led to a potential overestimation of the differences between polarization features when performing multiple pairwise comparisons and prevented multivariate analysis. Because of its compatibility with clinical OFDI catheters, intravascular polarimetry can be readily applied to any patient eligible for conventional OFDI, and future well-designed studies are needed to ascertain our current findings.
Second, our plaque classification corresponds well to the current understanding of plaque subtypes in OFDI (6) and could be readily performed on the conventional OFDI signal, yet conventional OFDI has limited ability to classify lesion types, especially in advanced lesions (11,14). Although lipid-rich plaques offer some prognostic implication (8), clear identification of fibroatheromas with OCT or OFDI remains debatable. Combination of intravascular ultrasound and OCT or OFDI has been shown to improve diagnostic accuracy of identifying fibroatheromas (13). Future histopathologic validation studies are needed to inspect the ability of polarization properties to distinguish between different plaque types and potentially enable automated plaque classification.
Third, we observed that the NSD was associated with depolarization in the focal fibrous caps but not in the entire caps. Macrophage infiltration frequently occurs very locally, and averaging the signals across entire caps carries less meaning than across a local region of interest. Moreover, the required normalization of the NSD depends delicately on the ROI, and evidence supporting the NSD metric remains scant. We suspect that both NSD and depolarization capture aspects of macrophage infiltration, but validation studies with histology are needed to identify how depolarization relates to macrophage infiltration.
Finally, no patient in the present study had plaque erosion, the second most common cause of ACS.
This study presents polarization properties of coronary atherosclerotic lesions in patients with coronary artery disease. The fibrous caps of culprit lesions in patients with ACS and/or PR featured lower birefringence than in those with SAP. When averaged across entire cross sections, the polarimetric signals varied among distinct morphological plaque subtypes. Quantitative assessment of plaque polarization properties by intravascular polarimetry may open new avenues for studying plaque composition and detecting high-risk patients. Prospective studies in larger populations are needed to evaluate how polarization metrics could translate into improved patient outcomes and optimized medical therapy compared with using only the structural features available to conventional OFDI.
COMPETENCY IN MEDICAL KNOWLEDGE: Modification of the OFDI apparatus along with recently developed image reconstruction methods enabled measurements of polarization properties of the coronary arterial wall. Intravascular polarimetry permits the quantitative assessment of polarization properties using standard intravascular OFDI catheters simultaneously with intensity image cross sections. This first-in-human pilot study of intravascular polarimetry demonstrated that polarization properties differ between culprit lesions of ACS or PR and SAP and also among different morphological plaque subtypes.
TRANSLATIONAL OUTLOOK: Quantitative assessment of plaque structure and composition by intravascular polarimetry may open new avenues for studying coronary atherosclerosis and may facilitate the automated interpretation of lesion characteristics during percutaneous coronary intervention in patients. Future studies are needed to investigate how intravascular polarimetry may improve invasive and pharmacological interventions in patients with coronary artery disease.
The authors sincerely thank Dr. Peter Libby of Brigham and Women’s Hospital and Harvard Medical School for fruitful discussion and feedback on this paper. Dr. Hang Lee, of the Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, provided invaluable guidance with respect to the statistical analyses in this work.
This work was supported by the National Institutes of Health (grants P41EB-015903 and R01HL-119065) and by Terumo Corporation. Dr. Bouma was supported in part by the Professor Andries Querido visiting professorship of the Erasmus University Medical Center in Rotterdam. Dr. Otsuka acknowledges partial support from the Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad, the Uehara Memorial Foundation Postdoctoral Fellowship, and the Japan Society for the Promotion of Science Overseas Research Fellowship. Massachusetts General Hospital and the Erasmus University Medical Center have patent licensing arrangements with Terumo Corporation. Drs. Bouma, van Soest, and Villiger have the right to receive royalties as part of the licensing arrangements. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndrome(s)
- fibrocalcified plaque
- fibrofatty plaque
- fibrous plaque
- normalized standard deviation
- optical coherence tomography
- optical frequency domain imaging
- plaque rupture
- stable angina pectoris
- thin-cap fibroatheroma
- thick-cap fibroatheroma
- Received January 22, 2019.
- Revision received April 24, 2019.
- Accepted June 11, 2019.
- 2019 The Authors
- Virmani R.,
- Burke A.P.,
- Farb A.,
- Kolodgie F.D.
- Narula J.,
- Nakano M.,
- Virmani R.,
- et al.
- Tearney G.J.,
- Yabushita H.,
- Houser S.L.,
- et al.
- Toutouzas K.,
- Karanasos A.,
- Tsiamis E.,
- et al.
- Tearney G.J.,
- Regar E.,
- Akasaka T.,
- et al.
- Arbab-Zadeh A.,
- Fuster V.
- Xing L.,
- Higuma T.,
- Wang Z.,
- et al.
- Zhang B.C.,
- Karanasos A.,
- Gnanadesigan M.,
- et al.
- Garcia-Garcia H.M.,
- Jang I.K.,
- Serruys P.W.,
- Kovacic J.C.,
- Narula J.,
- Fayad Z.A.
- Phipps J.E.,
- Vela D.,
- Hoyt T.,
- et al.
- Nakano M.,
- Yahagi K.,
- Yamamoto H.,
- et al.
- Phipps J.E.,
- Hoyt T.,
- Vela D.,
- et al.
- Villiger M.,
- Otsuka K.,
- Karanasos A.,
- et al.
- Villiger M.,
- Otsuka K.,
- Karanasos A.,
- et al.
- Nadkarni S.K.,
- Pierce M.C.,
- Park B.H.,
- et al.
- Lippok N.,
- Villiger M.,
- Albanese A.,
- et al.