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Potential contribution of virtual histology plaque composition to hemodynamic–morphologic dissociation in patients with non-ST elevation acute coronary syndrome
International Journal of Cardiology 187 (2015) 33–38
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Potential contribution of virtual histology plaque composition to hemodynamic–morphologic dissociation in patients with non-ST elevation acute coronary syndrome Güneş Hüseyinova a, Emre Aslanger b, Ozan Çakır a, Adem Atıcı a, Cafer Panç a, Ahmet Demirkıran a, Semih Sürmen a, Remzi Sarıkaya a, Onur Erdoğan a, Ebru Gölcük b, Sabahattin Umman a, Murat Sezer b,⁎ a b
Istanbul University, Istanbul Faculty of Medicine, Department of Cardiology, Turkey Koç University School of Medicine, Department of Cardiology, Turkey
a r t i c l e
i n f o
Article history: Received 10 January 2015 Received in revised form 18 March 2015 Accepted 20 March 2015 Available online 21 March 2015 Keywords: Coronary flow Intravascular ultrasound (IVUS) Plaque rupture Virtual histology
a b s t r a c t Objective: Histologic plaque characteristics may influence the hemodynamic effect generated by physiologically significant unstable coronary lesions where plaque content and surface related factors are expected to contribute to the maximum translesional pressure drop. In this study, we aimed to identify local lesion specific virtual histological characteristics that may potentially affect hemodynamic outcome measures. Methods: Forty-eight consecutive patients with non-ST-elevation acute coronary syndrome (NSTEACS) having paired hemodynamic and morphological data were enrolled. A dual sensor guide-wire was used for the assessment of fractional flow reserve (FFR) and stenosis resistance (HSR) in the culprit vessel. Virtual histology intravascular ultrasound imaging was performed after obtaining hemodynamic data. Results: In a hemodynamically significant lesion subset (FFR b 0.75 [n = 34]), after controlling for lesion length, MLA and coronary artery compliance, FFR correlated with necrotic core (NC) area (r = −0.423, p = 0.028) at MLA and NC volume (r = −0.497, p = 0.008) and dense calcium (DC) volume (r = −0.332, p = 0.03) across the entire lesion segment. Likewise, NC (r = −0.544, p = 0.005) and DC (r = 0.376, p = 0.03) areas at MLA and NC (r = 0.545, p = 0.005) and DC (r = 0.576, p = 0.003) volumes across the entire lesion segment were associated with HSR in the hemodynamically significant lesion group (HSR N 0.80 [n = 33]). However, no correlation has been observed between intracoronary hemodynamic end-points and plaque components in hemodynamically insignificant lesions. Conclusions: This study demonstrated that for a given coronary stenosis geometry and arterial compliance, plaque composition may influence hemodynamic outcome measures in functionally significant stenoses in patients with NSTEACS. © 2015 Published by Elsevier Ireland Ltd.
1. Introduction Lesion specific invasive indices, such as fractional flow reserve (FFR) and hyperemic stenosis resistance (HSR), are widely accepted as indispensible tools in the evaluation of hemodynamic significance of coronary stenoses. Lesion and vessel related factors such as lesion eccentricity, length [1] and vessel compliance [2,3] may influence the hemodynamic effect produced by a given coronary stenosis. To this end, ⁎ Corresponding author at: Koç University, School of Medicine, Department of Cardiology, Rumelifeneri Yolu, 34450 Sariyer, İstanbul, Turkey. E-mail addresses: [email protected] (G. Hüseyinova), [email protected] (E. Aslanger), [email protected] (O. Çakır), [email protected] (A. Atıcı), [email protected] (C. Panç), [email protected] (A. Demirkıran), [email protected] (S. Sürmen), [email protected] (R. Sarıkaya), [email protected] (O. Erdoğan), [email protected] (E. Gölcük), [email protected] (S. Umman), [email protected], [email protected] (M. Sezer).
http://dx.doi.org/10.1016/j.ijcard.2015.03.316 0167-5273/© 2015 Published by Elsevier Ireland Ltd.
unraveling potential influences of stenosis related morphological and geometric factors on epicardial conductance, and in turn FFR and HSR, may contribute significantly to our understanding concerning the interplay between an anatomical substrate and its physiological consequence. In the literature, howewer, there are only a few studies examining the possible impact of the geometry and composition of the coronary plaques on their hemodynamic effects [4–6]. Identification of the anatomical/morphological characteristics of coronary plaques such as plaque composition and rupture [7], lesion length and eccentricity [8], arterial wall compliance [2,3] and plaque composition, all of which may influence the hemodynamic effect of a given stenosis, can be possible with the aid of intravascular ultrasound imaging combining spectral analysis of radiofrequency ultrasound backscatter signals by virtual histology (VH-IVUS) [9]. In this study, we hypothesized that coronary plaque characteristics may contribute to the hemodynamic effect generated by stenoses, particularly the ones classified as physiologically significant, in which plaque surface
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related frictional loses are expected to contribute to the maximum translesional pressure drop. We, therefore, aimed to identify local lesion specific virtual histological characteristics that may potentially affect hemodynamic outcome measures such as FFR and HSR. 2. Methods 2.1. Patient population Fifty-four consecutive patients with non-ST-elevation acute coronary syndrome (NSTEACS) undergoing clinically indicated coronary angiography between January 2014 and June 2014 were prospectively enrolled for intracoronary hemodynamic evaluation by pressure and flow measurement and VH-IVUS imaging. Patients with previous coronary artery by-pass surgery and severe valvular disease were not included in the study. The study was conducted in accordance with the Declaration of Helsinki, and the local ethical review board approved the study protocol. Written informed consent was obtained from all patients. 2.2. Study protocol 2.2.1. Intracoronary hemodynamic measurements For the assessment of the hemodynamic significance of a given coronary stenosis, a dual-sensor guide-wire having a Doppler crystal at the tip and a pressure sensor 1.5 cm before the tip (Combo Wire, Volcano Corporation), was advanced across the lesion. Aortic pressure (Pa) was obtained from the guiding catheter and distal coronary pressure (Pd) and average peak flow velocity (APV) were assessed with the dual-sensor guide wire. All hemodynamic signals were recorded at baseline and during maximum hyperemia induced by a bolus of intracoronary papaverine (15 mg for the right coronary artery and 20 mg for the left coronary artery). Pressure and flow velocity signals were recorded on a device console (Combo Map, Volcano Corporation) during the procedure and extracted from the digital archive and analyzed offline. FFR was calculated as the ratio of mean distal coronary pressure to mean aortic pressure during maximum hyperemia. A velocity-pressure based index of HSR was calculated as the mean hyperemic stenosis pressure gradient across stenosis (Pa–Pd) divided by hyperemic APV distal to the stenosis. 2.2.2. IVUS and VH-IVUS imaging After obtaining hemodynamic measurements, the IVUS catheter (Eagle Eye Gold, Volcano Corporation) was advanced over the dual sensor tipped guide wire and automated pull back was performed at a speed of 0.5 mm/s. Quantitative gray scale and VH-IVUS analyses were performed and reported at the site of a minimum lumen area (MLA) and across the entire lesion segment according to consensus document recommendations in interpretation and reporting VH-IVUS parameters [10]. External elastic membrane (EEM) and lumen cross-sectional area (CSA) were measured. Plaque plus media (P&M) CSA was calculated as EEM minus lumen CSA and plaque burden at the MLA site was calculated as P&M divided by EEM CSA; volumes were calculated using Simpson's rule. Remodeling was assessed by means of the remodeling index (RI), expressed as the external elastic membrane CSA (MLA site) divided by the reference external elastic membrane CSA. The 4 VHIVUS plaque components (fibrous, fibro-fatty, dense calcium, and necrotic core) were measured in every recorded frame in the entire diseased segment and expressed as absolute amounts and as a percentage of plaque area or plaque volume. We have also calculated a necrotic core to dense calcium ratio. VH-IVUS derived thin cap fibro-atheroma (TCFA) was defined as a lesion meeting the following two criteria in at least three consecutive frames: (1) focal necrotic core-rich lesions (N10%) without evident overlying fibrous tissue and (2) % plaque-volume N 40%. We calculated coronary artery wall compliance at proximal reference site based on the external elastic lamina (EEM) dimensions measured on
three different time for each and averaged. Measurements were made at two points in the cardiac cycle at each position; immediately before the onset of the Q wave (end-diastole) and at the peak of the T wave (systole). Differences in EEM area were calculated over the cardiac cycle (Δarea). Cross-sectional compliance (mm2 mm Hg−1) was calculated as systolic–diastolic EEM area divided by pulse pressure (PP). Distal intracoronary pressures obtained from Combowire were used in the calculation of compliance for the coronary segments distal to the stenosis. Cross-sectional compliance coefficient (mm2 mm Hg−1) was calculated as systolic–diastolic EEM areas at proximal and distal reference segments divided by PP. Normalized compliances were calculated for proximal and distal reference segments as follows: [11] ½ðSystolic EEM area–diastolic EEM areaÞ=diastolic EEM area Pressure difference 3 −1 : 10 mm Hg
2.2.3. Statistical analysis Statistical tests were performed with the Statistical Package for the Social Sciences version 17.0 program (SPSS Inc., Chicago, Illinois). Continuous variables were expressed as mean ± standard deviation. Relationships between continuous variables were examined by using Pearson correlation or linear regression analysis. Relations between hemodynamic parameters (FFR, HSR) and plaque components were examined by controlling for anatomical factors that may affect hemodynamic outcomes including IVUS MLA, lesion length and EEM compliance by using partial correlation analysis. Significance was accepted as p b 0.05. 3. Results 3.1. Patient characteristics Obtaining reliable Doppler envelopes, meaning the adequate waveform, could be possible in 48 patients for which paired pressure waveforms and VH-IVUS images were also available. Therefore, a total of 48 lesions, which had paired hemodynamic and morphological data, were evaluated. Patient demographics and angiographic findings were summarized in Table 1. A total of 35 lesions (73%) were treated with percutaneous coronary intervention after hemodynamic and morphologic Table 1 Patient characteristics (n = 48). Clinical and demographical characteristics Male, n (%) Age Diabetes mellitus, n (%) Chronic kidney disease, n (%) Hypertension, n (%) Smoking, n (%) Total cholesterol level (mg/dL) LDL cholesterol level (mg/dL) HDL cholesterol level (mg/dL) Triglyceride level (mg/dL) Ejection fraction, % Angiographic characteristics Coronary vessels, n (%) LAD Diagonal Intermediate Circumflex RCA Stenosis location, n (%) Proximal Mid Distal Angiographic (visually estimated) stenosis, (%) Stent length, mean (mm) LAD, left anterior descending artery; RCA: right coronary artery.
35 (73) 58.1 ± 11.5 16 (33) 7 (14) 21 (44) 33 (69) 205.2 ± 42.3 128.6 ± 36.2 38.9 ± 10.2 182.3 ± 74.5 50.8 ± 7.3 25 (52) 2 (4) 2 (4) 6 (13) 13 (27) 30 16 2 65.8 ± 15.8 18.6 ± 5.7
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evaluation. Majority of the stenosis evaluated in this study were located in left anterior descending artery. No left main coronary artery lesions were observed in the patients with lesions in left coronary system. 3.2. Hemodynamic and morphological findings Hemodynamic data were presented in Table 2. Mean value of FFR was 0.65 ± 0.14 and mean HSR was 1.36 ± 1.14 mm Hg·cm−1·s−1. Using the established ischemic cut-points for FFR (0.75) and HSR (0.80), 34 and 33 lesions, respectively, were classified as hemodynamically significant. FFR strongly correlated with HSR as expected (r = −0.85, p b 0.001). Gray scale and VH-IVUS characteristics were listed in Table 3. The mean minimal luminal area was 2.5 mm2. The remodeling index correlated with necrotic core volume in the entire segment (r = 0.321, p = 0.03). MLA modestly correlated with FFR (r = 0.33, p = 0.008) and HSR (r = −0.39, p = 0.002). Indeed, correlations between lesion length and FFR (r = 0.38, p = 0.004) and HSR (r = 0.41, p = 0.002) were more prominent. The averaged normalized EEM compliance coefficient was 1.82 ± 1.15 mm Hg−1 and showed a positive correlation with RI (r = 0.38, p = 0.020). The EEM compliance had inverse correlation with dense calcium volume (r = −0.39, p = 0.001) (Fig. 1). There was no correlation between any other VH-IVUS parameters and compliance. 3.3. The relationship between VH-IVUS defined plaque components and hemodynamic outcome measures In the whole group consisting of both hemodynamically significant and non-significant lesions, there was no significant correlation between FFR and HSR and VH-IVUS defined plaque characteristics after controlling for potential confounders (MLA, lesion length and EEM compliance) using partial correlation. However, in the hemodynamically significant lesion subset (FFR b 0.75 [n = 34]), after controlling for MLA, lesion length and EEM compliance, FFR correlated with necrotic core (NC) area (r = −0.423, p = 0.028) at MLA and NC volume (r = −0.497, p = 0.008) and DC volume (r = −0.332, p = 0.03) across the entire lesion segment (Fig. 2). Nevertheless, there was no correlation between FFR and any of the plaque components in the hemodynamically non-significant lesion subset (FFR ≥ 0.75). Likewise, NC (r = −0.544, p = 0.005) and DC (r = 0.376, p = 0.03) areas at MLA and NC (r = 0.545, p = 0.005) and DC (r = 0.576, p = 0.003) volumes across the entire lesion segment were associated with HSR in the hemodynamically significant lesion group (HSR N 0.80) after controlling for the above stated confounding factors (Fig. 3). But, again, no relationship has been observed between plaque components and HSR in the hemodynamically non-significant (HSR ≤ 0.80) lesion subset. In the hemodynamically significant lesion group (n = 33), which was constituted according to the HSR threshold of N 0.80, 19 lesions had TCFA. In this hemodynamically significant lesion group, the
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Table 3 Intracoronary ultrasonographic characteristics (n = 48). Gray scale measurements At the minimum luminal CSA EEM (mm2) P + M (mm2) Plaque burden (%) MLA (mm2) Volumetric analysis EEM volume (mm3) Luminal volume (mm3) P + M volume (mm3) Other gray scale IVUS data Lesion length (mm) Reference EEM CSA (mm2) RMI EEM compliance (mm2 mm Hg−1 × 103) VH measurements At the minimum luminal CSA Fibrous area Fibro-fatty area Necrotic core area Dense calcium area NC/DC areas Volumetric analysis Fibrous volume Fibro-fatty volume Necrotic core volume Dense calcium volume NC/DC volumes
13.02 ± 4.49 10.2 ± 3.2 79.23 ± 6.7 2.51 ± 0.71 189.8 ± 27.4 52.1 ± 17.5 138.5 ± 72.5 16.73 ± 8.03 11.87 ± 4.19 1.15 ± 0.34 1.82 ± 1.15 mm2
% 56.6 ± 14.1 15.07 ± 12.3 19.7 ± 9.0 7.0 ± 10.5 4.8 ± 3.9 55.6 ± 9.1 15.7 ± 12.1 20.4 + 7.5 8.4 ± 8 3.9 ± 2.9
4.7 ± 2.5 1.2 ± 1.1 1.7 ± 1.2 0.5 ± 0.5
56.5 ± 35.5 14.3 ± 11.6 24 ± 20.5 8 ± 6.8
CSA: cross sectional area, EEM: external elastic membrane, P: plaque, M: media, MLA: minimal luminal area, VH: virtual histology, NC: necrotic core, DC: dense calcium, IVUS: intravascular ultrasonography, RMI: remodeling index.
presence of TCFA was associated with significantly higher HSR (2.15 ± 1.4 versus 1.32 ± 0.5, p = 0.03) and lower FFR (0.61 ± 0.15 versus 0.71 ± 0.07, p = 0.03) values compared to the absence of TCFA (Fig. 4). 4. Discussion This study is the first to demonstrate that composition of a given coronary stenosis can influence its hemodynamic consequence. In particular, NC and DC contents were independently associated with both FFR and HSR values in hemodynamically significant stenoses. It has been demonstrated that for a given stenosis geometry and arterial compliance, FFR values decrease and HSR values increase with an increase in
Table 2 Intracoronary hemodynamic measurements. Total (n: 48) Pamean, baseline Pamean, hyperemic Pdmean, baseline Pdmean, hyperemic APVmean, baseline APVmean, hyperemic FFRmean HSRmean CFRmean Pa: mean aortic pressure. Pd: mean distal intracoronary pressure. APV: average peak velocity. FFR: fractional flow reserve. HSR: hyperemic stenosis resistance.
106.4 ± 15.1 98.6 ± 15.4 81.7 ± 25.4 64.3 ± 20.6 21.78 ± 9.88 27.97 ± 14.12 0.65 ± 0.14 1.36 ± 1.14 1.31 ± 0.36
Fig. 1. The relationship between EEM compliance and dense calcium volume (DCvolume).
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Fig. 2. The relationship between fractional flow reserve (FFR) and plaque components in the hemodynamically significant lesion subset. DCvolume: dense calcium volume. NCvolume: necrotic core volume.
NC and DC contents of the physiologically significant coronary plaques. However, plaque composition did not exert any influence on the hemodynamic effect generated by the subcritical lesions. In the literature, there are only three studies investigating the possible hemodynamic impact of VH-IVUS defined morphological features of coronary plaques [4–6]. In these studies, it has been shown that composition of a given coronary stenosis may not have a significant impact on its hemodynamic effects assessed by FFR. Our findings both partly confirmed and extended the results of prior studies with substantial differences. Firstly, previous studies evaluated only intermediate stenoses mostly in patients presented with stable angina pectoris, whereas our study predominantly included physiologically significant lesions from unstable patients, which are known to be distinctly different from the stable ones [12,13,22]. Unstable plaques can be expected to exhibit frequent micro-ruptures and fissures on their surface, large NC content and high frequency of TCFA [14], all of which can contribute to surface irregularity that may eventually affect the hemodynamic consequence of a plaque mainly by increasing frictional energy loss. Secondly, in prior studies, the hemodynamic effect generated by the stenosis was assessed only by pressure based FFR measurements, which can be influenced by flow perturbations caused by other factors, such as microvascular dysfunction. However, in the current study, the hemodynamic impact of a given stenosis was assessed using pressure based (FFR) and pressureflow based (HSR) indices, both of which concordantly pointed out that plaque components may influence hemodynamic consequences in physiologically significant lesions. Thirdly, previous studies did not control the substantial influence of MLA and lesion length on FFR
measurement while examining the potential link between the histopathological characteristics of the plaque and their hemodynamic relevance. In the current study, we utilized partial correlation analysis to control major stenosis related geometric factors and a vessel wall related factor (compliance), in order to delineate the independent effect of VH-IVUS defined histopathological plaque characteristics on hemodynamic outcome measures. Several additional findings emerge as important observations in our study. In addition to classical determinants of the pressure drop across a lesion, like MLA and lesion length, we have also taken EEM compliance into consideration while examining the potential relationship between FFR/HSR and coronary plaque composition. Although the compliance of coronary arteries is so small to be considered as a potentially influential factor on the coronary hemodynamics; i.e., the diameter of the coronary artery changes by only b15% in normal pressure ranges [15], it may exert a remarkable effect on hemodynamic endpoints in the severely stenotic coronary segments particularly in the unstable plaques [2], where coronary compliance is known to be much higher compared to their stable counterparts [16]. In the present study, inverse correlation detected between DC volume and arterial compliance may support the concept that plaque content may influence hemodynamic outcomes by causing changes in vessel compliance. In line with our findings, it has been previously shown that there was a negative correlation between EEM compliance and magnitude of calcification [3,17]. Therefore, correlation demonstrated between calcium content and magnitude of ischemia generated by the stenosis may be attributed to the calcium induced decrease in arterial compliance.
Fig. 3. The relationship between hyperemic stenosis resistance (HSR) and plaque components in the hemodynamically significant lesion subset. DCvolume: dense calcium volume. NCvolume: necrotic core volume.
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5. Limitations This study included a relatively small number of patients from a single center. The main limitation of this study is related with the limited resolution of VH-IVUS in detecting small ruptures and fissures that may result in an increase in resistance to flow via changing surface properties. Therefore, potential factors that could have mainly affected surface properties and that may underlie the link between virtual histological characteristics and hemodynamic impact of a given coronary stenosis were not determined directly. Secondly, we calculated the compliance of coronary arteries by using a two-dimensional imaging technique and were not able to measure volumetric compliance. Since coronary compliance is so small and difficult to calculate particularly when two dimensional imaging techniques such as IVUS are used to measure changes in coronary diameters in a cardiac cycle, we could have underestimated the compliance values. But, in order to avoid this drawback, we measured compliance in multiple regions (both proximal and distal to the lesion) and averaged. Lastly, heavily calcified plaques may induce an artifact regarding the classification of plaques by VHIVUS resulting in an increase in NC content [21]. 6. Conclusion
Fig. 4. Impact of the presence of thin-cap fibroatheroma (TCFA) on hemodynamic endpoints [hyperemic stenosis resistance (HSR) and fractional flow reserve (FFR)] in the hemodynamically significant (HSR b 0.80) stenosis group.
Lastly, ultrasonographically detectable or undetectable plaque disruption/rupture may also influence the functional severity of the stenosis by causing increased surface roughness [7,8]. Although the detection of ruptured plaque based on IVUS imaging is doubtful considering limited resolution of this modality, it is known that the presence of plaque rupture has been demonstrated to be associated with the presence of TCFA and large necrotic core content. It can be anticipated that an emerging intravascular imaging modality, optical coherence tomography (OCT) with a resolution of 10–20 μm, can detect plaque erosion and rupture more frequently [18,19]. In the current study, the presence of TCFA was associated with higher HSR and lower FFR values in the hemodynamically significant lesion subset. In line with our findings, in a recent study, the presence of OCT-derived TCFA and the reduced fibrous cap thickness were shown to be related with lower FFR values [20]. Hence, the presence of TCFA may indeed contribute to the dissociation of morphological findings from the hemodynamic consequence. Accordingly, in the Fractional Flow Reserve and Intravascular Ultrasound Study (FIRST) [5], correlation between MLA and FFR was weaker in lesions with TCFA or calcified TCFA compared to those without. Although the FIRST study was also not able to demonstrate a contribution of plaque morphology at a determining level on ischemia generated by stenosis, this finding was derived only from an intermediate lesion subset in a stable coronary artery disease setting. In the current study, plaque components may have influenced the hemodynamic impact of a significant coronary lesion mainly by: 1) affecting surface properties (necrotic core component and TFCA); micro-ruptures, fissures, erosions may have contributed surface roughness that may generate a greater resistance to flow and/or 2) affecting vessel wall compliance (dense calcium component). These mechanisms may cooperatively operate particularly in hemodynamically significant unstable plaques where lesion or vessel wall related factors are expected to contribute translesional energy loss and pressure gradient at the highest level.
This study demonstrated that for a given coronary stenosis geometry and arterial compliance, plaque composition may have influence upon hemodynamic outcome measures in functionally significant stenoses. Specifically, VH-IVUS-determined necrotic core and TFCA, potentially by influencing surface morphology, and dense calcium content, potentially by affecting vessel wall compliance, may influence the hemodynamic consequence of any given physiologically significant stenosis. Conflict of interest None. Acknowledgements This study was partly supported by the Turkish Academy of Sciences. References [1] R. Lopez-Palop, P. Carrilo, A. Cordero, A. Frutos, I. Mateo, S. Mashlab, J. Roldan, Effect of lesion length on functional significance of intermediate long coronary lesions, Catheter. Cardiovasc. Interv. 81 (2013) E186–E194. [2] B.C. Konala, A. Das, R.K. Banerjee, Influence of arterial wall-stenosis compliance on the coronary diagnostic parameters, J. Biomech. 44 (2011) 842–847. [3] Y. Ishihara, M. Kawasaki, A. Hattori, H. Imai, S. Takahashi, H. Sato, T. Kubota, M. Okubo, S. Ojio, K. Nishigaki, G. Takemura, H. Fujiwara, S. Minatoguchi, Relationship among coronary plaque compliance, coronary risk factors and tissue characteristics evaluated by integrated backscatter intravascular ultrasound, Cardiovasc. Ultrasound 10 (2012) 32. [4] S. Brugeletta, H.M. Garcia-Garcia, Z.J. Shen, J. Gomez-Lara, R. Diletti, G. Sarno, N. Gonzalo, W. Wijns, B. de Bruyne, F. Alfonso, P.W. Serruys, Morphology of coronary artery lesions assessed by virtual histology intravascular ultrasound tissue characterization and fractional flow reserve, Int. J. Cardiovasc. Imaging 28 (2012) 221–228. [5] R. Waksman, J. Legutko, J. Singh, Q. Orlando, S. Marso, T. Schloss, J. Tugaoen, J. DeVries, N. Palmer, M. Haude, S. Swymelar, R. Torguson, FIRST: fractional flow reserve and intravascular ultrasound relationship study, J. Am. Coll. Cardiol. 61 (2013) 917–923. [6] J.H. Rogers, J. Wegelin, K. Harder, R. Valente, R. Low, Assessment of FFR-negative intermediate coronary artery stenoses by spectral analysis of the radiofrequency intravascular ultrasound signal, J. Invasive Cardiol. 18 (2008) 448–453. [7] S.J. Kang, A.J.M. Lee JY, H.G. Song, W.J. Kim, D.W. Park, S.C. Yun, S.W. Lee, Y.H. Kim, G.S. Mintz, C.W. Lee, S.W. Park, S.J. Park, Intravascular ultrasound derived predictors for fractional flow reserve in intermediate left main disease, JACC Cardiovasc. Interv. 4 (2011) 1168–1174. [8] S.J. Park, S.J. Kang, J.M. Ahn, E.B. Shim, Y.T. Kim, S.C. Yun, H. Song, J.Y. Lee, W.J. Kim, D.W. Park, S.W. Lee, Y.H. Kim, C.W. Lee, G.S. Mintz, S.W. Park, Visual–functional mismatch between coronary angiography and fractional flow reserve, JACC Cardiovasc. Interv. 5 (2012) 1029–1036. [9] A. Nair, B.D. Kuban, E.M. Tuzcu, P. Scoenhagen, S.E. Nissen, D.G. Vince, Coronary plaque classification with intravascular ultrasound radiofrequency data analysis, Circulation 106 (2002) 2200–2206.
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Potential contribution of virtual histology plaque composition to hemodynamic–morphologic dissociation in patients with non-ST elevation acute coronary syndrome Güneş Hüseyinova a, Emre Aslanger b, Ozan Çakır a, Adem Atıcı a, Cafer Panç a, Ahmet Demirkıran a, Semih Sürmen a, Remzi Sarıkaya a, Onur Erdoğan a, Ebru Gölcük b, Sabahattin Umman a, Murat Sezer b,⁎ a b
Istanbul University, Istanbul Faculty of Medicine, Department of Cardiology, Turkey Koç University School of Medicine, Department of Cardiology, Turkey
a r t i c l e
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Article history: Received 10 January 2015 Received in revised form 18 March 2015 Accepted 20 March 2015 Available online 21 March 2015 Keywords: Coronary flow Intravascular ultrasound (IVUS) Plaque rupture Virtual histology
a b s t r a c t Objective: Histologic plaque characteristics may influence the hemodynamic effect generated by physiologically significant unstable coronary lesions where plaque content and surface related factors are expected to contribute to the maximum translesional pressure drop. In this study, we aimed to identify local lesion specific virtual histological characteristics that may potentially affect hemodynamic outcome measures. Methods: Forty-eight consecutive patients with non-ST-elevation acute coronary syndrome (NSTEACS) having paired hemodynamic and morphological data were enrolled. A dual sensor guide-wire was used for the assessment of fractional flow reserve (FFR) and stenosis resistance (HSR) in the culprit vessel. Virtual histology intravascular ultrasound imaging was performed after obtaining hemodynamic data. Results: In a hemodynamically significant lesion subset (FFR b 0.75 [n = 34]), after controlling for lesion length, MLA and coronary artery compliance, FFR correlated with necrotic core (NC) area (r = −0.423, p = 0.028) at MLA and NC volume (r = −0.497, p = 0.008) and dense calcium (DC) volume (r = −0.332, p = 0.03) across the entire lesion segment. Likewise, NC (r = −0.544, p = 0.005) and DC (r = 0.376, p = 0.03) areas at MLA and NC (r = 0.545, p = 0.005) and DC (r = 0.576, p = 0.003) volumes across the entire lesion segment were associated with HSR in the hemodynamically significant lesion group (HSR N 0.80 [n = 33]). However, no correlation has been observed between intracoronary hemodynamic end-points and plaque components in hemodynamically insignificant lesions. Conclusions: This study demonstrated that for a given coronary stenosis geometry and arterial compliance, plaque composition may influence hemodynamic outcome measures in functionally significant stenoses in patients with NSTEACS. © 2015 Published by Elsevier Ireland Ltd.
1. Introduction Lesion specific invasive indices, such as fractional flow reserve (FFR) and hyperemic stenosis resistance (HSR), are widely accepted as indispensible tools in the evaluation of hemodynamic significance of coronary stenoses. Lesion and vessel related factors such as lesion eccentricity, length [1] and vessel compliance [2,3] may influence the hemodynamic effect produced by a given coronary stenosis. To this end, ⁎ Corresponding author at: Koç University, School of Medicine, Department of Cardiology, Rumelifeneri Yolu, 34450 Sariyer, İstanbul, Turkey. E-mail addresses: [email protected] (G. Hüseyinova), [email protected] (E. Aslanger), [email protected] (O. Çakır), [email protected] (A. Atıcı), [email protected] (C. Panç), [email protected] (A. Demirkıran), [email protected] (S. Sürmen), [email protected] (R. Sarıkaya), [email protected] (O. Erdoğan), [email protected] (E. Gölcük), [email protected] (S. Umman), [email protected], [email protected] (M. Sezer).
http://dx.doi.org/10.1016/j.ijcard.2015.03.316 0167-5273/© 2015 Published by Elsevier Ireland Ltd.
unraveling potential influences of stenosis related morphological and geometric factors on epicardial conductance, and in turn FFR and HSR, may contribute significantly to our understanding concerning the interplay between an anatomical substrate and its physiological consequence. In the literature, howewer, there are only a few studies examining the possible impact of the geometry and composition of the coronary plaques on their hemodynamic effects [4–6]. Identification of the anatomical/morphological characteristics of coronary plaques such as plaque composition and rupture [7], lesion length and eccentricity [8], arterial wall compliance [2,3] and plaque composition, all of which may influence the hemodynamic effect of a given stenosis, can be possible with the aid of intravascular ultrasound imaging combining spectral analysis of radiofrequency ultrasound backscatter signals by virtual histology (VH-IVUS) [9]. In this study, we hypothesized that coronary plaque characteristics may contribute to the hemodynamic effect generated by stenoses, particularly the ones classified as physiologically significant, in which plaque surface
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related frictional loses are expected to contribute to the maximum translesional pressure drop. We, therefore, aimed to identify local lesion specific virtual histological characteristics that may potentially affect hemodynamic outcome measures such as FFR and HSR. 2. Methods 2.1. Patient population Fifty-four consecutive patients with non-ST-elevation acute coronary syndrome (NSTEACS) undergoing clinically indicated coronary angiography between January 2014 and June 2014 were prospectively enrolled for intracoronary hemodynamic evaluation by pressure and flow measurement and VH-IVUS imaging. Patients with previous coronary artery by-pass surgery and severe valvular disease were not included in the study. The study was conducted in accordance with the Declaration of Helsinki, and the local ethical review board approved the study protocol. Written informed consent was obtained from all patients. 2.2. Study protocol 2.2.1. Intracoronary hemodynamic measurements For the assessment of the hemodynamic significance of a given coronary stenosis, a dual-sensor guide-wire having a Doppler crystal at the tip and a pressure sensor 1.5 cm before the tip (Combo Wire, Volcano Corporation), was advanced across the lesion. Aortic pressure (Pa) was obtained from the guiding catheter and distal coronary pressure (Pd) and average peak flow velocity (APV) were assessed with the dual-sensor guide wire. All hemodynamic signals were recorded at baseline and during maximum hyperemia induced by a bolus of intracoronary papaverine (15 mg for the right coronary artery and 20 mg for the left coronary artery). Pressure and flow velocity signals were recorded on a device console (Combo Map, Volcano Corporation) during the procedure and extracted from the digital archive and analyzed offline. FFR was calculated as the ratio of mean distal coronary pressure to mean aortic pressure during maximum hyperemia. A velocity-pressure based index of HSR was calculated as the mean hyperemic stenosis pressure gradient across stenosis (Pa–Pd) divided by hyperemic APV distal to the stenosis. 2.2.2. IVUS and VH-IVUS imaging After obtaining hemodynamic measurements, the IVUS catheter (Eagle Eye Gold, Volcano Corporation) was advanced over the dual sensor tipped guide wire and automated pull back was performed at a speed of 0.5 mm/s. Quantitative gray scale and VH-IVUS analyses were performed and reported at the site of a minimum lumen area (MLA) and across the entire lesion segment according to consensus document recommendations in interpretation and reporting VH-IVUS parameters [10]. External elastic membrane (EEM) and lumen cross-sectional area (CSA) were measured. Plaque plus media (P&M) CSA was calculated as EEM minus lumen CSA and plaque burden at the MLA site was calculated as P&M divided by EEM CSA; volumes were calculated using Simpson's rule. Remodeling was assessed by means of the remodeling index (RI), expressed as the external elastic membrane CSA (MLA site) divided by the reference external elastic membrane CSA. The 4 VHIVUS plaque components (fibrous, fibro-fatty, dense calcium, and necrotic core) were measured in every recorded frame in the entire diseased segment and expressed as absolute amounts and as a percentage of plaque area or plaque volume. We have also calculated a necrotic core to dense calcium ratio. VH-IVUS derived thin cap fibro-atheroma (TCFA) was defined as a lesion meeting the following two criteria in at least three consecutive frames: (1) focal necrotic core-rich lesions (N10%) without evident overlying fibrous tissue and (2) % plaque-volume N 40%. We calculated coronary artery wall compliance at proximal reference site based on the external elastic lamina (EEM) dimensions measured on
three different time for each and averaged. Measurements were made at two points in the cardiac cycle at each position; immediately before the onset of the Q wave (end-diastole) and at the peak of the T wave (systole). Differences in EEM area were calculated over the cardiac cycle (Δarea). Cross-sectional compliance (mm2 mm Hg−1) was calculated as systolic–diastolic EEM area divided by pulse pressure (PP). Distal intracoronary pressures obtained from Combowire were used in the calculation of compliance for the coronary segments distal to the stenosis. Cross-sectional compliance coefficient (mm2 mm Hg−1) was calculated as systolic–diastolic EEM areas at proximal and distal reference segments divided by PP. Normalized compliances were calculated for proximal and distal reference segments as follows: [11] ½ðSystolic EEM area–diastolic EEM areaÞ=diastolic EEM area Pressure difference 3 −1 : 10 mm Hg
2.2.3. Statistical analysis Statistical tests were performed with the Statistical Package for the Social Sciences version 17.0 program (SPSS Inc., Chicago, Illinois). Continuous variables were expressed as mean ± standard deviation. Relationships between continuous variables were examined by using Pearson correlation or linear regression analysis. Relations between hemodynamic parameters (FFR, HSR) and plaque components were examined by controlling for anatomical factors that may affect hemodynamic outcomes including IVUS MLA, lesion length and EEM compliance by using partial correlation analysis. Significance was accepted as p b 0.05. 3. Results 3.1. Patient characteristics Obtaining reliable Doppler envelopes, meaning the adequate waveform, could be possible in 48 patients for which paired pressure waveforms and VH-IVUS images were also available. Therefore, a total of 48 lesions, which had paired hemodynamic and morphological data, were evaluated. Patient demographics and angiographic findings were summarized in Table 1. A total of 35 lesions (73%) were treated with percutaneous coronary intervention after hemodynamic and morphologic Table 1 Patient characteristics (n = 48). Clinical and demographical characteristics Male, n (%) Age Diabetes mellitus, n (%) Chronic kidney disease, n (%) Hypertension, n (%) Smoking, n (%) Total cholesterol level (mg/dL) LDL cholesterol level (mg/dL) HDL cholesterol level (mg/dL) Triglyceride level (mg/dL) Ejection fraction, % Angiographic characteristics Coronary vessels, n (%) LAD Diagonal Intermediate Circumflex RCA Stenosis location, n (%) Proximal Mid Distal Angiographic (visually estimated) stenosis, (%) Stent length, mean (mm) LAD, left anterior descending artery; RCA: right coronary artery.
35 (73) 58.1 ± 11.5 16 (33) 7 (14) 21 (44) 33 (69) 205.2 ± 42.3 128.6 ± 36.2 38.9 ± 10.2 182.3 ± 74.5 50.8 ± 7.3 25 (52) 2 (4) 2 (4) 6 (13) 13 (27) 30 16 2 65.8 ± 15.8 18.6 ± 5.7
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evaluation. Majority of the stenosis evaluated in this study were located in left anterior descending artery. No left main coronary artery lesions were observed in the patients with lesions in left coronary system. 3.2. Hemodynamic and morphological findings Hemodynamic data were presented in Table 2. Mean value of FFR was 0.65 ± 0.14 and mean HSR was 1.36 ± 1.14 mm Hg·cm−1·s−1. Using the established ischemic cut-points for FFR (0.75) and HSR (0.80), 34 and 33 lesions, respectively, were classified as hemodynamically significant. FFR strongly correlated with HSR as expected (r = −0.85, p b 0.001). Gray scale and VH-IVUS characteristics were listed in Table 3. The mean minimal luminal area was 2.5 mm2. The remodeling index correlated with necrotic core volume in the entire segment (r = 0.321, p = 0.03). MLA modestly correlated with FFR (r = 0.33, p = 0.008) and HSR (r = −0.39, p = 0.002). Indeed, correlations between lesion length and FFR (r = 0.38, p = 0.004) and HSR (r = 0.41, p = 0.002) were more prominent. The averaged normalized EEM compliance coefficient was 1.82 ± 1.15 mm Hg−1 and showed a positive correlation with RI (r = 0.38, p = 0.020). The EEM compliance had inverse correlation with dense calcium volume (r = −0.39, p = 0.001) (Fig. 1). There was no correlation between any other VH-IVUS parameters and compliance. 3.3. The relationship between VH-IVUS defined plaque components and hemodynamic outcome measures In the whole group consisting of both hemodynamically significant and non-significant lesions, there was no significant correlation between FFR and HSR and VH-IVUS defined plaque characteristics after controlling for potential confounders (MLA, lesion length and EEM compliance) using partial correlation. However, in the hemodynamically significant lesion subset (FFR b 0.75 [n = 34]), after controlling for MLA, lesion length and EEM compliance, FFR correlated with necrotic core (NC) area (r = −0.423, p = 0.028) at MLA and NC volume (r = −0.497, p = 0.008) and DC volume (r = −0.332, p = 0.03) across the entire lesion segment (Fig. 2). Nevertheless, there was no correlation between FFR and any of the plaque components in the hemodynamically non-significant lesion subset (FFR ≥ 0.75). Likewise, NC (r = −0.544, p = 0.005) and DC (r = 0.376, p = 0.03) areas at MLA and NC (r = 0.545, p = 0.005) and DC (r = 0.576, p = 0.003) volumes across the entire lesion segment were associated with HSR in the hemodynamically significant lesion group (HSR N 0.80) after controlling for the above stated confounding factors (Fig. 3). But, again, no relationship has been observed between plaque components and HSR in the hemodynamically non-significant (HSR ≤ 0.80) lesion subset. In the hemodynamically significant lesion group (n = 33), which was constituted according to the HSR threshold of N 0.80, 19 lesions had TCFA. In this hemodynamically significant lesion group, the
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Table 3 Intracoronary ultrasonographic characteristics (n = 48). Gray scale measurements At the minimum luminal CSA EEM (mm2) P + M (mm2) Plaque burden (%) MLA (mm2) Volumetric analysis EEM volume (mm3) Luminal volume (mm3) P + M volume (mm3) Other gray scale IVUS data Lesion length (mm) Reference EEM CSA (mm2) RMI EEM compliance (mm2 mm Hg−1 × 103) VH measurements At the minimum luminal CSA Fibrous area Fibro-fatty area Necrotic core area Dense calcium area NC/DC areas Volumetric analysis Fibrous volume Fibro-fatty volume Necrotic core volume Dense calcium volume NC/DC volumes
13.02 ± 4.49 10.2 ± 3.2 79.23 ± 6.7 2.51 ± 0.71 189.8 ± 27.4 52.1 ± 17.5 138.5 ± 72.5 16.73 ± 8.03 11.87 ± 4.19 1.15 ± 0.34 1.82 ± 1.15 mm2
% 56.6 ± 14.1 15.07 ± 12.3 19.7 ± 9.0 7.0 ± 10.5 4.8 ± 3.9 55.6 ± 9.1 15.7 ± 12.1 20.4 + 7.5 8.4 ± 8 3.9 ± 2.9
4.7 ± 2.5 1.2 ± 1.1 1.7 ± 1.2 0.5 ± 0.5
56.5 ± 35.5 14.3 ± 11.6 24 ± 20.5 8 ± 6.8
CSA: cross sectional area, EEM: external elastic membrane, P: plaque, M: media, MLA: minimal luminal area, VH: virtual histology, NC: necrotic core, DC: dense calcium, IVUS: intravascular ultrasonography, RMI: remodeling index.
presence of TCFA was associated with significantly higher HSR (2.15 ± 1.4 versus 1.32 ± 0.5, p = 0.03) and lower FFR (0.61 ± 0.15 versus 0.71 ± 0.07, p = 0.03) values compared to the absence of TCFA (Fig. 4). 4. Discussion This study is the first to demonstrate that composition of a given coronary stenosis can influence its hemodynamic consequence. In particular, NC and DC contents were independently associated with both FFR and HSR values in hemodynamically significant stenoses. It has been demonstrated that for a given stenosis geometry and arterial compliance, FFR values decrease and HSR values increase with an increase in
Table 2 Intracoronary hemodynamic measurements. Total (n: 48) Pamean, baseline Pamean, hyperemic Pdmean, baseline Pdmean, hyperemic APVmean, baseline APVmean, hyperemic FFRmean HSRmean CFRmean Pa: mean aortic pressure. Pd: mean distal intracoronary pressure. APV: average peak velocity. FFR: fractional flow reserve. HSR: hyperemic stenosis resistance.
106.4 ± 15.1 98.6 ± 15.4 81.7 ± 25.4 64.3 ± 20.6 21.78 ± 9.88 27.97 ± 14.12 0.65 ± 0.14 1.36 ± 1.14 1.31 ± 0.36
Fig. 1. The relationship between EEM compliance and dense calcium volume (DCvolume).
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Fig. 2. The relationship between fractional flow reserve (FFR) and plaque components in the hemodynamically significant lesion subset. DCvolume: dense calcium volume. NCvolume: necrotic core volume.
NC and DC contents of the physiologically significant coronary plaques. However, plaque composition did not exert any influence on the hemodynamic effect generated by the subcritical lesions. In the literature, there are only three studies investigating the possible hemodynamic impact of VH-IVUS defined morphological features of coronary plaques [4–6]. In these studies, it has been shown that composition of a given coronary stenosis may not have a significant impact on its hemodynamic effects assessed by FFR. Our findings both partly confirmed and extended the results of prior studies with substantial differences. Firstly, previous studies evaluated only intermediate stenoses mostly in patients presented with stable angina pectoris, whereas our study predominantly included physiologically significant lesions from unstable patients, which are known to be distinctly different from the stable ones [12,13,22]. Unstable plaques can be expected to exhibit frequent micro-ruptures and fissures on their surface, large NC content and high frequency of TCFA [14], all of which can contribute to surface irregularity that may eventually affect the hemodynamic consequence of a plaque mainly by increasing frictional energy loss. Secondly, in prior studies, the hemodynamic effect generated by the stenosis was assessed only by pressure based FFR measurements, which can be influenced by flow perturbations caused by other factors, such as microvascular dysfunction. However, in the current study, the hemodynamic impact of a given stenosis was assessed using pressure based (FFR) and pressureflow based (HSR) indices, both of which concordantly pointed out that plaque components may influence hemodynamic consequences in physiologically significant lesions. Thirdly, previous studies did not control the substantial influence of MLA and lesion length on FFR
measurement while examining the potential link between the histopathological characteristics of the plaque and their hemodynamic relevance. In the current study, we utilized partial correlation analysis to control major stenosis related geometric factors and a vessel wall related factor (compliance), in order to delineate the independent effect of VH-IVUS defined histopathological plaque characteristics on hemodynamic outcome measures. Several additional findings emerge as important observations in our study. In addition to classical determinants of the pressure drop across a lesion, like MLA and lesion length, we have also taken EEM compliance into consideration while examining the potential relationship between FFR/HSR and coronary plaque composition. Although the compliance of coronary arteries is so small to be considered as a potentially influential factor on the coronary hemodynamics; i.e., the diameter of the coronary artery changes by only b15% in normal pressure ranges [15], it may exert a remarkable effect on hemodynamic endpoints in the severely stenotic coronary segments particularly in the unstable plaques [2], where coronary compliance is known to be much higher compared to their stable counterparts [16]. In the present study, inverse correlation detected between DC volume and arterial compliance may support the concept that plaque content may influence hemodynamic outcomes by causing changes in vessel compliance. In line with our findings, it has been previously shown that there was a negative correlation between EEM compliance and magnitude of calcification [3,17]. Therefore, correlation demonstrated between calcium content and magnitude of ischemia generated by the stenosis may be attributed to the calcium induced decrease in arterial compliance.
Fig. 3. The relationship between hyperemic stenosis resistance (HSR) and plaque components in the hemodynamically significant lesion subset. DCvolume: dense calcium volume. NCvolume: necrotic core volume.
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5. Limitations This study included a relatively small number of patients from a single center. The main limitation of this study is related with the limited resolution of VH-IVUS in detecting small ruptures and fissures that may result in an increase in resistance to flow via changing surface properties. Therefore, potential factors that could have mainly affected surface properties and that may underlie the link between virtual histological characteristics and hemodynamic impact of a given coronary stenosis were not determined directly. Secondly, we calculated the compliance of coronary arteries by using a two-dimensional imaging technique and were not able to measure volumetric compliance. Since coronary compliance is so small and difficult to calculate particularly when two dimensional imaging techniques such as IVUS are used to measure changes in coronary diameters in a cardiac cycle, we could have underestimated the compliance values. But, in order to avoid this drawback, we measured compliance in multiple regions (both proximal and distal to the lesion) and averaged. Lastly, heavily calcified plaques may induce an artifact regarding the classification of plaques by VHIVUS resulting in an increase in NC content [21]. 6. Conclusion
Fig. 4. Impact of the presence of thin-cap fibroatheroma (TCFA) on hemodynamic endpoints [hyperemic stenosis resistance (HSR) and fractional flow reserve (FFR)] in the hemodynamically significant (HSR b 0.80) stenosis group.
Lastly, ultrasonographically detectable or undetectable plaque disruption/rupture may also influence the functional severity of the stenosis by causing increased surface roughness [7,8]. Although the detection of ruptured plaque based on IVUS imaging is doubtful considering limited resolution of this modality, it is known that the presence of plaque rupture has been demonstrated to be associated with the presence of TCFA and large necrotic core content. It can be anticipated that an emerging intravascular imaging modality, optical coherence tomography (OCT) with a resolution of 10–20 μm, can detect plaque erosion and rupture more frequently [18,19]. In the current study, the presence of TCFA was associated with higher HSR and lower FFR values in the hemodynamically significant lesion subset. In line with our findings, in a recent study, the presence of OCT-derived TCFA and the reduced fibrous cap thickness were shown to be related with lower FFR values [20]. Hence, the presence of TCFA may indeed contribute to the dissociation of morphological findings from the hemodynamic consequence. Accordingly, in the Fractional Flow Reserve and Intravascular Ultrasound Study (FIRST) [5], correlation between MLA and FFR was weaker in lesions with TCFA or calcified TCFA compared to those without. Although the FIRST study was also not able to demonstrate a contribution of plaque morphology at a determining level on ischemia generated by stenosis, this finding was derived only from an intermediate lesion subset in a stable coronary artery disease setting. In the current study, plaque components may have influenced the hemodynamic impact of a significant coronary lesion mainly by: 1) affecting surface properties (necrotic core component and TFCA); micro-ruptures, fissures, erosions may have contributed surface roughness that may generate a greater resistance to flow and/or 2) affecting vessel wall compliance (dense calcium component). These mechanisms may cooperatively operate particularly in hemodynamically significant unstable plaques where lesion or vessel wall related factors are expected to contribute translesional energy loss and pressure gradient at the highest level.
This study demonstrated that for a given coronary stenosis geometry and arterial compliance, plaque composition may have influence upon hemodynamic outcome measures in functionally significant stenoses. Specifically, VH-IVUS-determined necrotic core and TFCA, potentially by influencing surface morphology, and dense calcium content, potentially by affecting vessel wall compliance, may influence the hemodynamic consequence of any given physiologically significant stenosis. Conflict of interest None. Acknowledgements This study was partly supported by the Turkish Academy of Sciences. References [1] R. Lopez-Palop, P. Carrilo, A. Cordero, A. Frutos, I. Mateo, S. Mashlab, J. Roldan, Effect of lesion length on functional significance of intermediate long coronary lesions, Catheter. Cardiovasc. Interv. 81 (2013) E186–E194. [2] B.C. Konala, A. Das, R.K. Banerjee, Influence of arterial wall-stenosis compliance on the coronary diagnostic parameters, J. Biomech. 44 (2011) 842–847. [3] Y. Ishihara, M. Kawasaki, A. Hattori, H. Imai, S. Takahashi, H. Sato, T. Kubota, M. Okubo, S. Ojio, K. Nishigaki, G. Takemura, H. Fujiwara, S. Minatoguchi, Relationship among coronary plaque compliance, coronary risk factors and tissue characteristics evaluated by integrated backscatter intravascular ultrasound, Cardiovasc. Ultrasound 10 (2012) 32. [4] S. Brugeletta, H.M. Garcia-Garcia, Z.J. Shen, J. Gomez-Lara, R. Diletti, G. Sarno, N. Gonzalo, W. Wijns, B. de Bruyne, F. Alfonso, P.W. Serruys, Morphology of coronary artery lesions assessed by virtual histology intravascular ultrasound tissue characterization and fractional flow reserve, Int. J. Cardiovasc. Imaging 28 (2012) 221–228. [5] R. Waksman, J. Legutko, J. Singh, Q. Orlando, S. Marso, T. Schloss, J. Tugaoen, J. DeVries, N. Palmer, M. Haude, S. Swymelar, R. Torguson, FIRST: fractional flow reserve and intravascular ultrasound relationship study, J. Am. Coll. Cardiol. 61 (2013) 917–923. [6] J.H. Rogers, J. Wegelin, K. Harder, R. Valente, R. Low, Assessment of FFR-negative intermediate coronary artery stenoses by spectral analysis of the radiofrequency intravascular ultrasound signal, J. Invasive Cardiol. 18 (2008) 448–453. [7] S.J. Kang, A.J.M. Lee JY, H.G. Song, W.J. Kim, D.W. Park, S.C. Yun, S.W. Lee, Y.H. Kim, G.S. Mintz, C.W. Lee, S.W. Park, S.J. Park, Intravascular ultrasound derived predictors for fractional flow reserve in intermediate left main disease, JACC Cardiovasc. Interv. 4 (2011) 1168–1174. [8] S.J. Park, S.J. Kang, J.M. Ahn, E.B. Shim, Y.T. Kim, S.C. Yun, H. Song, J.Y. Lee, W.J. Kim, D.W. Park, S.W. Lee, Y.H. Kim, C.W. Lee, G.S. Mintz, S.W. Park, Visual–functional mismatch between coronary angiography and fractional flow reserve, JACC Cardiovasc. Interv. 5 (2012) 1029–1036. [9] A. Nair, B.D. Kuban, E.M. Tuzcu, P. Scoenhagen, S.E. Nissen, D.G. Vince, Coronary plaque classification with intravascular ultrasound radiofrequency data analysis, Circulation 106 (2002) 2200–2206.
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