International Journal of Cardiology 185 (2015) 56–61
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
The relationship between intravascular ultrasound-derived percent total atheroma volume and fractional flow reserve in the intermediate stenosis of proximal or middle left anterior descending coronary artery Xiong Jie Jin, Seung-Jea Tahk ⁎, Hyoung-Mo Yang, Hong-Seok Lim, Myeong-Ho Yoon, So-Yeon Choi, Byoung-Joo Choi, Gyo-Seung Hwang, Kyoung-Woo Seo, Jeoung-Sook Shin, You-Hong Lee, Yong-Woo Choi, Se-Jun Park, Jin-Sun Park, Joon-Han Shin Department of Cardiology, Ajou University School of Medicine, Suwon, Republic of Korea
a r t i c l e
i n f o
Article history: Received 7 May 2014 Received in revised form 25 October 2014 Accepted 3 March 2015 Available online 4 March 2015 Keywords: Fractional flow reserve Intravascular ultrasound Percent total atheroma volume
a b s t r a c t Background: It remains undefined whether the atherosclerotic disease extent of the conductive vessel (expressed as intravascular ultrasound [IVUS]-derived percent total atheroma volume [%TAV]), correlates with functional severity of intermediate stenosis of left anterior descending artery (LAD). Methods: An IVUS study and fractional flow reserve (FFR) measurements performed in 130 patients with coronary angiographic intermediate stenosis of proximal or middle LAD. %TAV was calculated as the percentage of total vessel volume occupied by total atheroma volume on IVUS. Results: A significant correlation was observed between %TAV and FFR (r = −0.71, p b 0.001). Minimal lumen area (MLA) correlated moderately with FFR (r = 0.54, p b 0.001). The independent predictors of FFR b 0.8 were %TAV (odds ratio [OR]: 1.29, 95% confidence interval [CI] = 1.18–1.40, p b 0.001) and MLA (OR: 0.37, 95% CI = 0.16–0.85, p = 0.019). A receiver-operating characteristic curve suggested %TAV ≥ 39.0% (sensitivity 85%, specificity 83% and area under curve [AUC] = 0.90) and MLA ≤ 2.6 mm2 (sensitivity 72%, specificity 70% and AUC = 0.75) as the best cut-off values for FFR b 0.8. Forty-eight point five (48.5%) of total studied lesions (63/130) showed %TAV ≥ 39.0%. Eighty-four point four (84.4%) of lesions (38/45) with %TAV ≥ 39.0% and MLA ≤ 2.6 mm2, and 72.2% of lesions (13/18) with %TAV ≥ 39.0% and MLA N 2.6 mm2, FFR was less than 0.8. Conclusions: Volumetric quantification of the atherosclerotic disease extent of the coronary artery, expressed as IVUS-derived %TAV, showed a strong correlation with FFR. Not only the segmental luminal narrowing but also the total plaque burden of conductive artery are major determinants for the presence of myocardial ischemia in intermediate stenosis of LAD. © 2015 Published by Elsevier Ireland Ltd.
1. Introduction Atherosclerosis is a diffuse systemic disease that often remains as an insignificant process on coronary angiography. Diffuse coronary atherosclerosis without visible stenosis on coronary angiography can significantly affect coronary flow hemodynamics by increasing the resistance of conductive vessels and contribute to myocardial ischemia [1]. Intravascular ultrasound (IVUS) provides not only the severity of segmental stenosis but also the diffuseness of the atherosclerotic process of the conductive vessel. However, it is practically difficult to
⁎ Corresponding author at: Department of Cardiology, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-gu, Suwon 443-380, Republic of Korea. E-mail address: [email protected] (S.-J. Tahk).
http://dx.doi.org/10.1016/j.ijcard.2015.03.048 0167-5273/© 2015 Published by Elsevier Ireland Ltd.
represent the diffuseness of disease with one IVUS-parameter. IVUSderived minimum lumen area (MLA) has a moderate correlation with fractional flow reserve (FFR) [2–6]; however, it represents only the severity of segmental stenosis confined to the culprit site. Therefore, IVUS-MLA cannot accurately reflect the functional significance of the entire conductive vessel, and it may overestimate or underestimate the functional significance of the entire disease process and lead to erroneous revascularization decisions [7,8]. The correlation between the diffuseness of atherosclerotic disease of the conductive vessel and FFR in patients with intermediate stenosis remains undefined. Therefore, we aimed to evaluate the relationship between the extent of atherosclerosis by IVUS, expressed as percent total atheroma volume (%TAV), which can be calculated from the ratio of total atheroma volume to total vessel volume on an IVUS study, and FFR in the left anterior descending coronary artery (LAD) in patients with intermediate stenosis.
X.J. Jin et al. / International Journal of Cardiology 185 (2015) 56–61
57
2.3. IVUS imaging and analysis
Table 1 Baseline clinical characteristics of the patients (n = 130). Characteristics
Value
Age (years) Male Clinical diagnosis Stable angina Unstable angina Others Diabetes mellitus Hypertension Hyperlipidemia Smoking Multivessel disease Left ventricular ejection fraction, %
61 ± 10 91 (70%) 67 (52%) 47 (36%) 16 (12%) 42 (32%) 56 (43%) 30 (23%) 21 (16%) 40 (31%) 65 ± 8
Values are mean ± SD or n (%).
2. Materials and methods 2.1. Study population We selected 130 patients with single de novo intermediate stenosis from January 2010 to December 2012 (40–70% diameter stenosis by visual estimation) of the proximal or middle segment of the LAD on diagnostic coronary angiography, and who underwent an IVUS study and FFR measurements with informed consent. Exclusion criteria were multiple stenosis (N40% diameter stenosis by visual estimation) in the same vessel, left main stenosis, left ventricular ejection fraction b 40%, the presence of a collateral vessel, contraindication to adenosine, previous coronary bypass surgery, and angiographically thrombi-containing lesions. In addition, patients with history and/or evidence of any myocardial infarction were excluded from the study. This study protocol was approved by the ethics committee of our institution.
2.2. Quantitative coronary angiographic analysis The quantitative coronary angiographic (QCA) analysis was performed using the cardiovascular angiography analysis system II (CAAS II, pie Medical, Maastricht, Netherlands). Diameter stenosis (DS), minimum lumen diameter (MLD), reference vessel diameter, and lesion length were measured. Lesion length was calculated as the distance between the proximal and distal reference in the projection demonstrating the stenosis with the least foreshortening.
IVUS was performed using the Galaxy 2™ IVUS system (Boston Scientific Corporation, Natick, MA, USA) after intracoronary bolus of 200 μg nitroglycerin. A 40-MHz coronary imaging IVUS catheter (Atlantis SR Pro, Natick, MA, USA) was pulled back from the distal LAD through the target stenosis to the ostium of the left main coronary artery using a motorized pullback device at a speed of 0.5 mm/s. All IVUS analyses were performed using computerized planimetry software (EchoPlaque 3.0, Indec Systems, Santa Clara, CA, USA) according to the American College of Cardiology Clinical Expert Consensus Document on Standards for acquisition, measurement and reporting of IVUS Studies [9]. We analyzed IVUS images spaced precisely 1 mm apart, with an average of 69.8 ± 14.9 mm per patient. When acoustic shadowing caused by lesion calcification made the identification of the external elastic membrane (EEM) difficult, circumferential or axial extrapolation was used [10]. Coronary arteries with calcium arc N 90° in the studied segments were excluded. MLA and external elastic membrane (EEM) were measured at the narrowest luminal cross section of the target lesion and the reference area at the most normal looking cross section within 10 mm proximal and distal to the lesion without an intervening side branch. Lesion length was defined as the region around the MLA where the lumen area was b50% of the reference lumen area [11]. Plaque burden at the narrowest site was calculated as [100 × (EEM area-MLA) / EEM area]. The atheroma area in each measured image was defined as the difference between the lumen area and the EEM area. Total atheroma volume (TAV) was calculated as the sum of plaque area and total vessel volume (TVV) as the summation of EEM area in all measured images [12]. 3 TAV mm ¼ ∑ ðEEM area−lumen areaÞ 3 TVV mm ¼ ∑ ðEEM areaÞ The extent of atherosclerosis was also expressed as the percent total atheroma volume (%TAV), calculated as the percentage of TVV occupied by TAV [12]. %TAVð%Þ ¼
TAV 100 TVV
We randomly selected 10 cases to assess interobserver variability for re-measuring IVUS cross-sectional images by an independent investigator. The interobserver correlation coefficients for TVV, total lumen volume and TAV were 0.97, 0.95 and 0.98, respectively [13].
Fig. 1. Relationship between FFR and angiographic parameters. A moderate correlation was observed between FFR and minimum lumen diameter (A)/diameter stenosis (B). FFR, fractional flow reserve.
58
X.J. Jin et al. / International Journal of Cardiology 185 (2015) 56–61
Table 2 BCV and AUC in ROC curves of angiographic and IVUS parameters in prediction of functionally significant stenosis in the LAD. BCV Angiographic parameters Minimum lumen diameter, mm Diameter stenosis, % IVUS parameters Minimum lumen area, mm2 Plaque burden, % Lesion length, mm % total atheroma volume, %
1.5 51.0
2.6 75.0 20.0 39.0
AUC 0.72 0.75
0.75 0.69 0.74 0.90
Table 3 BCV and AUC in ROC curve of angiographic and IVUS parameters in prediction of functionally significant stenosis according to lesion location in the LAD.
95% CI 0.63–0.79 0.67–0.82
0.66–0.82 0.60–0.77 0.65–0.81 0.83–0.94
AUC, area under the curve; BCV, best cut-off value; CI, confidence interval; IVUS, intravascular ultrasound; LAD, left anterior descending artery; ROC, receiver operating characteristic.
2.4. FFR measurement After the IVUS assessment, FFR was measured using a 0.014-inch pressure guide wire (Pressure Wire, Radi Medical Systems, Uppsala, Sweden). If necessary, additional intracoronary nitroglycerin was administered to prevent coronary spasm. “Equalizing” was performed with the pressure sensor positioned at the guiding catheter tip. A pressure wire then was advanced across the target lesion, and the pressuresensor was positioned at the same segment of the distal LAD where the IVUS pullback started. Then, the pressure wire was manually pulled back from the distal LAD through the target stenosis to the aorta to confirm the presence of pressure drift. FFR was calculated as the ratio of distal coronary pressure to aortic pressure during maximal hyperemia. Maximal hyperemia was induced by continuous intracoronary infusion of adenosine (N360 μg/min) via microcatheter for inducing more reliable sustained maximal hyperemia as described in our previous study [14]. FFR b 0.8 was considered functionally significant. 2.5. Statistical analysis Data are expressed as means ± standard deviations for continuous variables and frequency (percentage) for categorical variables. Comparison of continuous variables was performed using Student's t-test. The relationships between FFR and IVUS or QCA parameters were analyzed by Pearson's correlation analysis. Multivariate logistic regression analysis was performed to determine independent predictors of FFR b 0.8. Receiver operating characteristic (ROC) curves were analyzed to assess the best cut-off values (BCV) of IVUS and QCA parameters to determine FFR b 0.8. All statistical analyses were performed using SPSS ver. 18.0, Medcalc (Medicalc Software, Antwerp Belgium), and a p-value b 0.05 was considered significant. 3. Results 3.1. Baseline characteristics The baseline characteristics of the patients are summarized in Table 1. A total of 130 patients were analyzed. Sixty-seven (52%) of whom had stable angina, 47 (36%) had unstable angina, and the other 16 (12%) presented with atypical chest discomfort. Mean age was 61 ± 10 years; 42 (32%) patients had diabetes mellitus, 56 (43%) patients had hypertension, and 40 (31%) patients had multivessel disease. The echocardiographic left ventricular ejection fraction was 65 ± 8%. 3.2. FFR and QCA parameters FFR showed moderate correlations with angiographic MLD (r = 0.45, p b 0.001) and DS (r = − 0.44, p b 0.001) (Fig. 1). The best cutoff value (BCV) to predict FFR b 0.8 was 1.5 mm for angiographic MLD (sensitivity 67%, specificity 64%, positive predictive value [PPV] 66%,
Proximal LAD
Middle LAD
(n = 43)
(n = 87)
BCV
BCV
AUC 95% CI
AUC 95% CI
Angiographic parameters Minimum lumen diameter, mm 1.74 0.79 0.64–0.89 1.52 0.75 0.64–0.83 Diameter stenosis, % 49.0 0.71 0.56–0.84 54.0 0.78 0.68–0.86 IVUS parameters Minimum lumen area, mm2 Plaque burden, % Lesion length, mm % total atheroma volume, %
3.0 80.0 20.0 40.5
0.84 0.73 0.83 0.93
0.69–0.93 2.62 0.57–0.85 76.0 0.68–0.92 19.9 0.81–0.98 38.5
0.79 0.69 0.76 0.87
0.69–0.87 0.58–0.78 0.65–0.84 0.79–0.93
AUC, area under the curve; BCV, best cut-off value; CI, confidence interval; IVUS, intravascular ultrasound; LAD, left anterior descending artery; ROC, receiver operating characteristic.
negative predictive value [NPV] 69%, accuracy 65%, and area under curve [AUC]: 0.72), and 51% for angiographic DS (sensitivity 70%, specificity 69%, PPV 69%, NPV 73%, accuracy 70%, and AUC: 0.75) (Tables 2 and 4).
3.3. FFR and IVUS parameters FFR correlated moderately with MLA (r = 0.54, p b 0.001), plaque burden at the MLA site (r = − 0.46, p b 0.001), and lesion length (r = − 0.56, p b 0.001). FFR showed the most significant correlation with %TAV (r = −0.71, p b 0.001) (Fig. 2). Multivariate logistic regression analysis demonstrated MLA (odds ratio [OR] = 0.37, 95% confidence interval [CI], 0.16–0.85, p = 0.019) and %TAV (OR = 1.29, 95% CI, 1.18–1.40, p b 0.001) as independent predictors of FFR b 0.80 (Table 5). The BCV to predict FFR b 0.8 was 2.6 mm2 for MLA (sensitivity 72%, specificity 70%, PPV 72%, NPV 74%, accuracy 71%, and AUC 0.75), 20.0 mm for lesion length (sensitivity 70%, specificity 67%, PPV 70%, NPV 72%, accuracy 68%, and AUC 0.74), and 39.0% for %TAV (sensitivity 85%, specificity 83%, PPV 85%, NPV 87%, accuracy 84%, and AUC 0.90) (Tables 2 and 4, Fig. 3). In a subgroup analysis of proximal and middle LAD, the BCV of MLA to predict FFR b0.8 was 3.0 mm2 (AUC: 0.84, 95% CI: 0.69–0.93) in proximal LAD and it was 2.62 mm2 (AUC: 0.79, 95% CI: 0.69–0.87) in middle LAD. The BCV of %TAV to predict FFR b0.8 was 40.5% (AUC: 0.93, 95% CI: 0.81–0.98) in proximal LAD and it was 38.5% (AUC: 0.87, 95% CI: 0.79–0.93) in middle LAD (Table 3). Forty-eight point five (48.5%) of total studied lesions (63/130) showed %TAV ≥39.0%. Eighty-four point four (84.4%) of lesions (38/45) with %TAV ≥ 39.0% and MLA ≤ 2.6 mm2, and 72.2% of lesions (13/18) with %TAV ≥ 39.0% and MLA N 2.6 mm2, FFR was less than 0.8. In contrast, 8.3% of lesions (4/48) with %TAV b 39.0% and MLA N 2.6 mm2 showed FFR b 0.8 (Fig. 4).
Table 4 Diagnostic accuracy of angiographic and IVUS parameters for FFR b 0.80. Sensitivity
Specificity
PPV
NPV
Accuracy
Angiographic parameters Minimum lumen diameter Diameter stenosis
67% 70%
64% 69%
66% 69%
69% 73%
65% 70%
IVUS parameters Minimum lumen area Plaque burden Lesion length % total atheroma volume
72% 68% 70% 85%
70% 67% 67% 83%
72% 68% 70% 85%
74% 70% 72% 87%
71% 66% 68% 84%
FFR, fractional flow reserve; IVUS, intravascular ultrasound; NPV, negative predictive value; PPV, positive predictive value.
X.J. Jin et al. / International Journal of Cardiology 185 (2015) 56–61
59
Fig. 2. Relationship between FFR and IVUS parameters. The correlation was most highly significant between FFR and percent total atheroma volume (A), A moderate correlation was observed between FFR and minimum lumen area (B), plaque burden (C), and lesion length (D). FFR, fractional flow reserve; IVUS, intravascular ultrasound.
4. Discussion The major findings of the present study are as follows: In intermediate stenosis of LAD, (1) the extent of diffuseness atherosclerosis of conductive vessel, expressed as IVUS-derived %TAV, showed the most significant correlation with FFR, (2) %TAV ≥ 39.0% and MLA ≤ 2.6 mm2 were the best cut-off values for FFR b 0.80, (3) 48.5% of total studied lesions (63/130) showed %TAV ≥ 39.0%, which represents the diffuse atherosclerotic process limiting coronary blood flow. IVUS is the most commonly used adjunctive procedure during percutaneous coronary intervention and provides comprehensive morphological information of the conductive vessel. IVUS-MLA has been most frequently used to represent the severity of coronary stenosis. However, MLA confined to the culprit site and does not represent the atherosclerotic severity of the whole conductive artery. IVUS-MLA was considered as parameter with cutoff values that vary according to vessel size and lesion location, and even subgroup-specific criteria were inaccurate in identifying ischemia inducible stenosis [2–6].
Previous pathological and IVUS studies have shown that visible angiographic segmental coronary stenosis is usually associated with diffuse atherosclerosis in the remainder of the coronary tree, although this is often not identified by coronary angiography [15–17]. De Bruyne
Table 5 Multivariate analysis of independent factors for functionally significant stenosis (FFR b 0.8).
Minimum lumen area % total atheroma volume
OR
95% CI
p value
0.37 1.29
0.16–0.85 1.18–1.40
0.019 b0.001
CI, confidence interval; FFR, fractional flow reserve; OR, odds ratio. Included variables: minimum lumen area, plaque burden, lesion length, and % total atheroma volume.
Fig. 3. Comparison of ROC curves of IVUS parameters for functionally significant stenosis. Percent total atheroma volume had the best area under the curve among the IVUS-derived parameters. IVUS, intravascular ultrasound; MLA, minimum lumen area; %TAV, percent total atheroma volume; ROC, receiver operating characteristic.
60
X.J. Jin et al. / International Journal of Cardiology 185 (2015) 56–61
Fig. 4. Effect of MLA and %TAV on functionally significant stenosis (FFR b 0.8). In lesions with significant %TAV (≥39.0%) and MLA (≤2.6 mm2), 84.4% of lesions showed FFR b 0.8. In contrast, when both %TAV (b39.0%) and MLA (N2.6 mm2) were not significant, only 8.3% of lesions showed FFR b 0.8. FFR, fractional flow reserve; MLA, minimum lumen area; %TAV, percent total atheroma volume.
B et al. demonstrated that approximately half of coronary arteries without angiographic focal stenosis have a graded, continuous decline in coronary pressure along their length, particularly during hyperemia [1]. Therefore, we supposed that the discrepancy between IVUS-MLA and FFR results mainly originates from the hemodynamic effects of diffuse coronary atherosclerosis in other segments of the conductive artery. We traced the cross-sectional IVUS images of the conductive coronary vessel of interest using a pullback device at constant speed. Therefore, we could express the extent of diffuseness of the atherosclerotic process of nearly the entire conductive vessel using IVUS-derived %TAV. Percent total atheroma volume (%TAV) could represent not only the severity of segmental stenosis but also the extent of diffuseness of atherosclerosis, both of which may contribute to limit coronary flow. We demonstrated that the diagnostic accuracy of %TAV was 84% for predicting functional significance (FFR b 0.8) of intermediate coronary artery stenosis of LAD. The best cut-off value of %TAV was 39.0% with AUC of 0.90, and %TAV showed the best correlation with FFR among the IVUS-measured parameters that have been studied. As expected, %TAV was ≥ 39.0% in 48.5% of the patients, which means that about half of patients with intermediate stenosis of the LAD have diffuse disease that significantly influences the resistance of the conductive vessel. Additionally, MLA N 2.6 mm2 excluded the possibility of FFR b 0.80 with a sensitivity of 72% and a specificity of 70%. A moderate correlation was observed between MLA and FFR (r = 0.54, p b 0.001). These results are consistent with those of other recently published studies [2–6]. Both of %TAV (≥39.0%) and MLA (≤2.6 mm2) were significant in 34.6% of the patients (45/130), and 84.4% of them (38/45) showed FFR b 0.8. Both of %TAV (b39.0%) and MLA (N2.6 mm2) were not significant in 36.9% of the patients (48/130), and only 8.3% of them (4/48) showed FFR b 0.8. The present data confirmed that the diffuse atherosclerotic process could significantly affect the resistance of the conductive vessel and the amount of stress-induced maximal coronary flow regardless of segmental stenosis on angiography in patients with intermediate stenosis of LAD. Additionally, the degree of diffuseness, expressed by %TAV, showed an excellent correlation with FFR. Therefore, when evaluating the intermediate stenosis of the LAD by IVUS, we suggest that if diffuse coronary atherosclerosis exists in the entering vessel, regardless of whether MLA is significant or not, FFR should be measured to determine the presence of stress-induced myocardial ischemia. Study limitations: First, the findings of this study were based on a single-center. Second, although intracoronary nitroglycerin was given before IVUS measurement, the possibility of catheter and guidewire induced spasm or bias cannot be excluded. Third, calculating the total plaque volume of conductive vessel by tracing all the IVUS pullback images was time-consuming and laborious. If the software for rapid automatic volumetric measurement is available, our study would be helpful in guiding the clinical decision process for equivocal cases, especially with anatomic and functional mismatch. Fourth, the results of this study would not be applicable for all types of coronary artery lesions. Validation of %TAV in the various types of lesions at various coronary artery sites is needed. Finally, although intravenous adenosine infusion has been known as standard method for inducing maximal coronary
hyperemia for FFR measurement, this study adopted intracoronary continuous adenosine infusion via microcatheter. It has been validated as a safe and effective method in inducing maximal hyperemia compared to standard intravenous infusion method [14]. 5. Conclusions Volumetric quantification of the atherosclerotic disease extent of the coronary artery, expressed as IVUS-derived %TAV, showed a strong correlation with FFR. Not only the segmental luminal narrowing but also the total plaque burden of conductive artery are major determinants for the presence of myocardial ischemia in intermediate stenosis of the LAD. Conflict of interest There is no conflict of interest. References [1] B. De Bruyne, F. Hersbach, N.H. Pijls, et al., Abnormal epicardial coronary resistance in patients with diffuse atherosclerosis but “normal” coronary angiography, Circulation 104 (2001) 2401–2406. [2] B.K. Koo, H.M. Yang, J.H. Doh, et al., Optimal intravascular ultrasound criteria and their accuracy for defining the functional significance of intermediate coronary stenosis of different locations, JACC Cardiovasc. Interv. 4 (2011) 803–811. [3] S.J. Kang, J.Y. Lee, J.M. Ahn, et al., Validation of intravascular ultrasound-derived parameters with fractional flow reserve for assessment of coronary stenosis severity, Circ. Cardiovasc. Interv. 4 (2011) 65–71. [4] I. Ben-Dor, R. Torquson, M.A. Gaglia Jr., et al., Correlation between fractional flow reserve and intravascular ultrasound lumen area in intermediate coronary artery stenosis, EuroIntervention 7 (2011) 225–233. [5] S.J. Kang, J.M. Ahn, H. Song, et al., Usefulness of minimal luminal coronary area determined by intravascular ultrasound to predict functional significance in stable and unstable angina pectoris, Am. J. Cardiol. 109 (2012) 947–953. [6] R. Waksman, J. Legutko, J. Singh, et al., FIRST: fractional flow reserve and intravascular ultrasound relationship study, J. Am. Coll. Cardiol. 61 (2013) 917–923. [7] V. Magni, A. Chieffo, A. Colombo, Evaluation of intermediate coronary stenosis with intravascular ultrasound and fractional flow reserve: its use and abuse, Catheter. Cardiovasc. Interv. 73 (2009) 441–448. [8] C.W. Nam, H.J. Yoon, Y.K. Cho, et al., Outcomes of percutaneous coronary intervention in intermediate coronary artery disease, JACC Cardiovasc. Interv. 3 (2010) 812–817. [9] G.S. Mintz, S.E. Nissen, W.D. Anderson, et al., American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS): A report of the American College of Cardiology Task Force on Clinical Expert consensus Documents, J. Am. Coll. Cardiol. 37 (2001) 1478–1492. [10] G.S. Mintz, J.A. Kovach, S.P. Javier, et al., Mechanisms of lumen enlargement after excimer laser coronary angioplasty: an intravascular ultrasound study, Circulation 92 (1995) 3408–3414. [11] N. Gonzalo, J. Escaned, F. Alfonso, et al., Morphometric assessment of coronary stenosis relevance with optical coherence tomography: a comparison with fractional flow reserve and intravascular ultrasound, J. Am. Coll. Cardiol. 59 (2012) 1080–1089. [12] S.J. Nicholls, I. Sipahi, P. Schoenhagen, et al., Intravascular ultrasound assessment of novel antiatherosclerotic therapies: rationale and design of the Acyl-CoA: cholesterol acyltransferase intravascular atherosclerosis treatment evaluation (ACTIV-ATE) study, Am. Heart J. 152 (2006) 67–74. [13] M. Yamagishi, H. Hosokawa, S. Saito, et al., Coronary disease morphology and distribution determined by quantitative angiography and intravascular ultrasound:
X.J. Jin et al. / International Journal of Cardiology 185 (2015) 56–61 re-evaluation in a cooperative multicenter intravascular ultrasound study (COMIUS), Jpn. Circ. J. 66 (2002) 735–740. [14] M.H. Yoon, S.J. Tahk, H.M. Yang, et al., Comparison of the intracoronary continuous infusion method using a microcatheter and the intravenous continuous adenosine infusion method for inducing maximal hyperemia for fractional flow reserve measurement, Am. Heart J. 157 (2009) 1050–1056. [15] S. Glagov, E. Weisenberg, C.K. Zarins, R. Stankunavicius, G.J. Koletitis, Compensatory enlargement of human atherosclerotic coronary arteries, N. Engl. J. Med. 316 (1987) 1371–1375.
61
[16] S.E. Nissen, J.C. Gurley, C.L. Grines, et al., Intravascular ultrasound assessment of lumen size and wall morphology in normal subjects and patients with coronary artery disease, Circulation 84 (1991) 1087–1099. [17] G.S. Mintz, J.A. Painter, A.D. Pichard, et al., Atherosclerosis in angiographically “normal” coronary artery reference segments: an intravascular ultrasound study with. Clinical correlations, J. Am. Coll. Cardiol. 25 (1995) 1479–1485.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
The relationship between intravascular ultrasound-derived percent total atheroma volume and fractional flow reserve in the intermediate stenosis of proximal or middle left anterior descending coronary artery Xiong Jie Jin, Seung-Jea Tahk ⁎, Hyoung-Mo Yang, Hong-Seok Lim, Myeong-Ho Yoon, So-Yeon Choi, Byoung-Joo Choi, Gyo-Seung Hwang, Kyoung-Woo Seo, Jeoung-Sook Shin, You-Hong Lee, Yong-Woo Choi, Se-Jun Park, Jin-Sun Park, Joon-Han Shin Department of Cardiology, Ajou University School of Medicine, Suwon, Republic of Korea
a r t i c l e
i n f o
Article history: Received 7 May 2014 Received in revised form 25 October 2014 Accepted 3 March 2015 Available online 4 March 2015 Keywords: Fractional flow reserve Intravascular ultrasound Percent total atheroma volume
a b s t r a c t Background: It remains undefined whether the atherosclerotic disease extent of the conductive vessel (expressed as intravascular ultrasound [IVUS]-derived percent total atheroma volume [%TAV]), correlates with functional severity of intermediate stenosis of left anterior descending artery (LAD). Methods: An IVUS study and fractional flow reserve (FFR) measurements performed in 130 patients with coronary angiographic intermediate stenosis of proximal or middle LAD. %TAV was calculated as the percentage of total vessel volume occupied by total atheroma volume on IVUS. Results: A significant correlation was observed between %TAV and FFR (r = −0.71, p b 0.001). Minimal lumen area (MLA) correlated moderately with FFR (r = 0.54, p b 0.001). The independent predictors of FFR b 0.8 were %TAV (odds ratio [OR]: 1.29, 95% confidence interval [CI] = 1.18–1.40, p b 0.001) and MLA (OR: 0.37, 95% CI = 0.16–0.85, p = 0.019). A receiver-operating characteristic curve suggested %TAV ≥ 39.0% (sensitivity 85%, specificity 83% and area under curve [AUC] = 0.90) and MLA ≤ 2.6 mm2 (sensitivity 72%, specificity 70% and AUC = 0.75) as the best cut-off values for FFR b 0.8. Forty-eight point five (48.5%) of total studied lesions (63/130) showed %TAV ≥ 39.0%. Eighty-four point four (84.4%) of lesions (38/45) with %TAV ≥ 39.0% and MLA ≤ 2.6 mm2, and 72.2% of lesions (13/18) with %TAV ≥ 39.0% and MLA N 2.6 mm2, FFR was less than 0.8. Conclusions: Volumetric quantification of the atherosclerotic disease extent of the coronary artery, expressed as IVUS-derived %TAV, showed a strong correlation with FFR. Not only the segmental luminal narrowing but also the total plaque burden of conductive artery are major determinants for the presence of myocardial ischemia in intermediate stenosis of LAD. © 2015 Published by Elsevier Ireland Ltd.
1. Introduction Atherosclerosis is a diffuse systemic disease that often remains as an insignificant process on coronary angiography. Diffuse coronary atherosclerosis without visible stenosis on coronary angiography can significantly affect coronary flow hemodynamics by increasing the resistance of conductive vessels and contribute to myocardial ischemia [1]. Intravascular ultrasound (IVUS) provides not only the severity of segmental stenosis but also the diffuseness of the atherosclerotic process of the conductive vessel. However, it is practically difficult to
⁎ Corresponding author at: Department of Cardiology, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-gu, Suwon 443-380, Republic of Korea. E-mail address: [email protected] (S.-J. Tahk).
http://dx.doi.org/10.1016/j.ijcard.2015.03.048 0167-5273/© 2015 Published by Elsevier Ireland Ltd.
represent the diffuseness of disease with one IVUS-parameter. IVUSderived minimum lumen area (MLA) has a moderate correlation with fractional flow reserve (FFR) [2–6]; however, it represents only the severity of segmental stenosis confined to the culprit site. Therefore, IVUS-MLA cannot accurately reflect the functional significance of the entire conductive vessel, and it may overestimate or underestimate the functional significance of the entire disease process and lead to erroneous revascularization decisions [7,8]. The correlation between the diffuseness of atherosclerotic disease of the conductive vessel and FFR in patients with intermediate stenosis remains undefined. Therefore, we aimed to evaluate the relationship between the extent of atherosclerosis by IVUS, expressed as percent total atheroma volume (%TAV), which can be calculated from the ratio of total atheroma volume to total vessel volume on an IVUS study, and FFR in the left anterior descending coronary artery (LAD) in patients with intermediate stenosis.
X.J. Jin et al. / International Journal of Cardiology 185 (2015) 56–61
57
2.3. IVUS imaging and analysis
Table 1 Baseline clinical characteristics of the patients (n = 130). Characteristics
Value
Age (years) Male Clinical diagnosis Stable angina Unstable angina Others Diabetes mellitus Hypertension Hyperlipidemia Smoking Multivessel disease Left ventricular ejection fraction, %
61 ± 10 91 (70%) 67 (52%) 47 (36%) 16 (12%) 42 (32%) 56 (43%) 30 (23%) 21 (16%) 40 (31%) 65 ± 8
Values are mean ± SD or n (%).
2. Materials and methods 2.1. Study population We selected 130 patients with single de novo intermediate stenosis from January 2010 to December 2012 (40–70% diameter stenosis by visual estimation) of the proximal or middle segment of the LAD on diagnostic coronary angiography, and who underwent an IVUS study and FFR measurements with informed consent. Exclusion criteria were multiple stenosis (N40% diameter stenosis by visual estimation) in the same vessel, left main stenosis, left ventricular ejection fraction b 40%, the presence of a collateral vessel, contraindication to adenosine, previous coronary bypass surgery, and angiographically thrombi-containing lesions. In addition, patients with history and/or evidence of any myocardial infarction were excluded from the study. This study protocol was approved by the ethics committee of our institution.
2.2. Quantitative coronary angiographic analysis The quantitative coronary angiographic (QCA) analysis was performed using the cardiovascular angiography analysis system II (CAAS II, pie Medical, Maastricht, Netherlands). Diameter stenosis (DS), minimum lumen diameter (MLD), reference vessel diameter, and lesion length were measured. Lesion length was calculated as the distance between the proximal and distal reference in the projection demonstrating the stenosis with the least foreshortening.
IVUS was performed using the Galaxy 2™ IVUS system (Boston Scientific Corporation, Natick, MA, USA) after intracoronary bolus of 200 μg nitroglycerin. A 40-MHz coronary imaging IVUS catheter (Atlantis SR Pro, Natick, MA, USA) was pulled back from the distal LAD through the target stenosis to the ostium of the left main coronary artery using a motorized pullback device at a speed of 0.5 mm/s. All IVUS analyses were performed using computerized planimetry software (EchoPlaque 3.0, Indec Systems, Santa Clara, CA, USA) according to the American College of Cardiology Clinical Expert Consensus Document on Standards for acquisition, measurement and reporting of IVUS Studies [9]. We analyzed IVUS images spaced precisely 1 mm apart, with an average of 69.8 ± 14.9 mm per patient. When acoustic shadowing caused by lesion calcification made the identification of the external elastic membrane (EEM) difficult, circumferential or axial extrapolation was used [10]. Coronary arteries with calcium arc N 90° in the studied segments were excluded. MLA and external elastic membrane (EEM) were measured at the narrowest luminal cross section of the target lesion and the reference area at the most normal looking cross section within 10 mm proximal and distal to the lesion without an intervening side branch. Lesion length was defined as the region around the MLA where the lumen area was b50% of the reference lumen area [11]. Plaque burden at the narrowest site was calculated as [100 × (EEM area-MLA) / EEM area]. The atheroma area in each measured image was defined as the difference between the lumen area and the EEM area. Total atheroma volume (TAV) was calculated as the sum of plaque area and total vessel volume (TVV) as the summation of EEM area in all measured images [12]. 3 TAV mm ¼ ∑ ðEEM area−lumen areaÞ 3 TVV mm ¼ ∑ ðEEM areaÞ The extent of atherosclerosis was also expressed as the percent total atheroma volume (%TAV), calculated as the percentage of TVV occupied by TAV [12]. %TAVð%Þ ¼
TAV 100 TVV
We randomly selected 10 cases to assess interobserver variability for re-measuring IVUS cross-sectional images by an independent investigator. The interobserver correlation coefficients for TVV, total lumen volume and TAV were 0.97, 0.95 and 0.98, respectively [13].
Fig. 1. Relationship between FFR and angiographic parameters. A moderate correlation was observed between FFR and minimum lumen diameter (A)/diameter stenosis (B). FFR, fractional flow reserve.
58
X.J. Jin et al. / International Journal of Cardiology 185 (2015) 56–61
Table 2 BCV and AUC in ROC curves of angiographic and IVUS parameters in prediction of functionally significant stenosis in the LAD. BCV Angiographic parameters Minimum lumen diameter, mm Diameter stenosis, % IVUS parameters Minimum lumen area, mm2 Plaque burden, % Lesion length, mm % total atheroma volume, %
1.5 51.0
2.6 75.0 20.0 39.0
AUC 0.72 0.75
0.75 0.69 0.74 0.90
Table 3 BCV and AUC in ROC curve of angiographic and IVUS parameters in prediction of functionally significant stenosis according to lesion location in the LAD.
95% CI 0.63–0.79 0.67–0.82
0.66–0.82 0.60–0.77 0.65–0.81 0.83–0.94
AUC, area under the curve; BCV, best cut-off value; CI, confidence interval; IVUS, intravascular ultrasound; LAD, left anterior descending artery; ROC, receiver operating characteristic.
2.4. FFR measurement After the IVUS assessment, FFR was measured using a 0.014-inch pressure guide wire (Pressure Wire, Radi Medical Systems, Uppsala, Sweden). If necessary, additional intracoronary nitroglycerin was administered to prevent coronary spasm. “Equalizing” was performed with the pressure sensor positioned at the guiding catheter tip. A pressure wire then was advanced across the target lesion, and the pressuresensor was positioned at the same segment of the distal LAD where the IVUS pullback started. Then, the pressure wire was manually pulled back from the distal LAD through the target stenosis to the aorta to confirm the presence of pressure drift. FFR was calculated as the ratio of distal coronary pressure to aortic pressure during maximal hyperemia. Maximal hyperemia was induced by continuous intracoronary infusion of adenosine (N360 μg/min) via microcatheter for inducing more reliable sustained maximal hyperemia as described in our previous study [14]. FFR b 0.8 was considered functionally significant. 2.5. Statistical analysis Data are expressed as means ± standard deviations for continuous variables and frequency (percentage) for categorical variables. Comparison of continuous variables was performed using Student's t-test. The relationships between FFR and IVUS or QCA parameters were analyzed by Pearson's correlation analysis. Multivariate logistic regression analysis was performed to determine independent predictors of FFR b 0.8. Receiver operating characteristic (ROC) curves were analyzed to assess the best cut-off values (BCV) of IVUS and QCA parameters to determine FFR b 0.8. All statistical analyses were performed using SPSS ver. 18.0, Medcalc (Medicalc Software, Antwerp Belgium), and a p-value b 0.05 was considered significant. 3. Results 3.1. Baseline characteristics The baseline characteristics of the patients are summarized in Table 1. A total of 130 patients were analyzed. Sixty-seven (52%) of whom had stable angina, 47 (36%) had unstable angina, and the other 16 (12%) presented with atypical chest discomfort. Mean age was 61 ± 10 years; 42 (32%) patients had diabetes mellitus, 56 (43%) patients had hypertension, and 40 (31%) patients had multivessel disease. The echocardiographic left ventricular ejection fraction was 65 ± 8%. 3.2. FFR and QCA parameters FFR showed moderate correlations with angiographic MLD (r = 0.45, p b 0.001) and DS (r = − 0.44, p b 0.001) (Fig. 1). The best cutoff value (BCV) to predict FFR b 0.8 was 1.5 mm for angiographic MLD (sensitivity 67%, specificity 64%, positive predictive value [PPV] 66%,
Proximal LAD
Middle LAD
(n = 43)
(n = 87)
BCV
BCV
AUC 95% CI
AUC 95% CI
Angiographic parameters Minimum lumen diameter, mm 1.74 0.79 0.64–0.89 1.52 0.75 0.64–0.83 Diameter stenosis, % 49.0 0.71 0.56–0.84 54.0 0.78 0.68–0.86 IVUS parameters Minimum lumen area, mm2 Plaque burden, % Lesion length, mm % total atheroma volume, %
3.0 80.0 20.0 40.5
0.84 0.73 0.83 0.93
0.69–0.93 2.62 0.57–0.85 76.0 0.68–0.92 19.9 0.81–0.98 38.5
0.79 0.69 0.76 0.87
0.69–0.87 0.58–0.78 0.65–0.84 0.79–0.93
AUC, area under the curve; BCV, best cut-off value; CI, confidence interval; IVUS, intravascular ultrasound; LAD, left anterior descending artery; ROC, receiver operating characteristic.
negative predictive value [NPV] 69%, accuracy 65%, and area under curve [AUC]: 0.72), and 51% for angiographic DS (sensitivity 70%, specificity 69%, PPV 69%, NPV 73%, accuracy 70%, and AUC: 0.75) (Tables 2 and 4).
3.3. FFR and IVUS parameters FFR correlated moderately with MLA (r = 0.54, p b 0.001), plaque burden at the MLA site (r = − 0.46, p b 0.001), and lesion length (r = − 0.56, p b 0.001). FFR showed the most significant correlation with %TAV (r = −0.71, p b 0.001) (Fig. 2). Multivariate logistic regression analysis demonstrated MLA (odds ratio [OR] = 0.37, 95% confidence interval [CI], 0.16–0.85, p = 0.019) and %TAV (OR = 1.29, 95% CI, 1.18–1.40, p b 0.001) as independent predictors of FFR b 0.80 (Table 5). The BCV to predict FFR b 0.8 was 2.6 mm2 for MLA (sensitivity 72%, specificity 70%, PPV 72%, NPV 74%, accuracy 71%, and AUC 0.75), 20.0 mm for lesion length (sensitivity 70%, specificity 67%, PPV 70%, NPV 72%, accuracy 68%, and AUC 0.74), and 39.0% for %TAV (sensitivity 85%, specificity 83%, PPV 85%, NPV 87%, accuracy 84%, and AUC 0.90) (Tables 2 and 4, Fig. 3). In a subgroup analysis of proximal and middle LAD, the BCV of MLA to predict FFR b0.8 was 3.0 mm2 (AUC: 0.84, 95% CI: 0.69–0.93) in proximal LAD and it was 2.62 mm2 (AUC: 0.79, 95% CI: 0.69–0.87) in middle LAD. The BCV of %TAV to predict FFR b0.8 was 40.5% (AUC: 0.93, 95% CI: 0.81–0.98) in proximal LAD and it was 38.5% (AUC: 0.87, 95% CI: 0.79–0.93) in middle LAD (Table 3). Forty-eight point five (48.5%) of total studied lesions (63/130) showed %TAV ≥39.0%. Eighty-four point four (84.4%) of lesions (38/45) with %TAV ≥ 39.0% and MLA ≤ 2.6 mm2, and 72.2% of lesions (13/18) with %TAV ≥ 39.0% and MLA N 2.6 mm2, FFR was less than 0.8. In contrast, 8.3% of lesions (4/48) with %TAV b 39.0% and MLA N 2.6 mm2 showed FFR b 0.8 (Fig. 4).
Table 4 Diagnostic accuracy of angiographic and IVUS parameters for FFR b 0.80. Sensitivity
Specificity
PPV
NPV
Accuracy
Angiographic parameters Minimum lumen diameter Diameter stenosis
67% 70%
64% 69%
66% 69%
69% 73%
65% 70%
IVUS parameters Minimum lumen area Plaque burden Lesion length % total atheroma volume
72% 68% 70% 85%
70% 67% 67% 83%
72% 68% 70% 85%
74% 70% 72% 87%
71% 66% 68% 84%
FFR, fractional flow reserve; IVUS, intravascular ultrasound; NPV, negative predictive value; PPV, positive predictive value.
X.J. Jin et al. / International Journal of Cardiology 185 (2015) 56–61
59
Fig. 2. Relationship between FFR and IVUS parameters. The correlation was most highly significant between FFR and percent total atheroma volume (A), A moderate correlation was observed between FFR and minimum lumen area (B), plaque burden (C), and lesion length (D). FFR, fractional flow reserve; IVUS, intravascular ultrasound.
4. Discussion The major findings of the present study are as follows: In intermediate stenosis of LAD, (1) the extent of diffuseness atherosclerosis of conductive vessel, expressed as IVUS-derived %TAV, showed the most significant correlation with FFR, (2) %TAV ≥ 39.0% and MLA ≤ 2.6 mm2 were the best cut-off values for FFR b 0.80, (3) 48.5% of total studied lesions (63/130) showed %TAV ≥ 39.0%, which represents the diffuse atherosclerotic process limiting coronary blood flow. IVUS is the most commonly used adjunctive procedure during percutaneous coronary intervention and provides comprehensive morphological information of the conductive vessel. IVUS-MLA has been most frequently used to represent the severity of coronary stenosis. However, MLA confined to the culprit site and does not represent the atherosclerotic severity of the whole conductive artery. IVUS-MLA was considered as parameter with cutoff values that vary according to vessel size and lesion location, and even subgroup-specific criteria were inaccurate in identifying ischemia inducible stenosis [2–6].
Previous pathological and IVUS studies have shown that visible angiographic segmental coronary stenosis is usually associated with diffuse atherosclerosis in the remainder of the coronary tree, although this is often not identified by coronary angiography [15–17]. De Bruyne
Table 5 Multivariate analysis of independent factors for functionally significant stenosis (FFR b 0.8).
Minimum lumen area % total atheroma volume
OR
95% CI
p value
0.37 1.29
0.16–0.85 1.18–1.40
0.019 b0.001
CI, confidence interval; FFR, fractional flow reserve; OR, odds ratio. Included variables: minimum lumen area, plaque burden, lesion length, and % total atheroma volume.
Fig. 3. Comparison of ROC curves of IVUS parameters for functionally significant stenosis. Percent total atheroma volume had the best area under the curve among the IVUS-derived parameters. IVUS, intravascular ultrasound; MLA, minimum lumen area; %TAV, percent total atheroma volume; ROC, receiver operating characteristic.
60
X.J. Jin et al. / International Journal of Cardiology 185 (2015) 56–61
Fig. 4. Effect of MLA and %TAV on functionally significant stenosis (FFR b 0.8). In lesions with significant %TAV (≥39.0%) and MLA (≤2.6 mm2), 84.4% of lesions showed FFR b 0.8. In contrast, when both %TAV (b39.0%) and MLA (N2.6 mm2) were not significant, only 8.3% of lesions showed FFR b 0.8. FFR, fractional flow reserve; MLA, minimum lumen area; %TAV, percent total atheroma volume.
B et al. demonstrated that approximately half of coronary arteries without angiographic focal stenosis have a graded, continuous decline in coronary pressure along their length, particularly during hyperemia [1]. Therefore, we supposed that the discrepancy between IVUS-MLA and FFR results mainly originates from the hemodynamic effects of diffuse coronary atherosclerosis in other segments of the conductive artery. We traced the cross-sectional IVUS images of the conductive coronary vessel of interest using a pullback device at constant speed. Therefore, we could express the extent of diffuseness of the atherosclerotic process of nearly the entire conductive vessel using IVUS-derived %TAV. Percent total atheroma volume (%TAV) could represent not only the severity of segmental stenosis but also the extent of diffuseness of atherosclerosis, both of which may contribute to limit coronary flow. We demonstrated that the diagnostic accuracy of %TAV was 84% for predicting functional significance (FFR b 0.8) of intermediate coronary artery stenosis of LAD. The best cut-off value of %TAV was 39.0% with AUC of 0.90, and %TAV showed the best correlation with FFR among the IVUS-measured parameters that have been studied. As expected, %TAV was ≥ 39.0% in 48.5% of the patients, which means that about half of patients with intermediate stenosis of the LAD have diffuse disease that significantly influences the resistance of the conductive vessel. Additionally, MLA N 2.6 mm2 excluded the possibility of FFR b 0.80 with a sensitivity of 72% and a specificity of 70%. A moderate correlation was observed between MLA and FFR (r = 0.54, p b 0.001). These results are consistent with those of other recently published studies [2–6]. Both of %TAV (≥39.0%) and MLA (≤2.6 mm2) were significant in 34.6% of the patients (45/130), and 84.4% of them (38/45) showed FFR b 0.8. Both of %TAV (b39.0%) and MLA (N2.6 mm2) were not significant in 36.9% of the patients (48/130), and only 8.3% of them (4/48) showed FFR b 0.8. The present data confirmed that the diffuse atherosclerotic process could significantly affect the resistance of the conductive vessel and the amount of stress-induced maximal coronary flow regardless of segmental stenosis on angiography in patients with intermediate stenosis of LAD. Additionally, the degree of diffuseness, expressed by %TAV, showed an excellent correlation with FFR. Therefore, when evaluating the intermediate stenosis of the LAD by IVUS, we suggest that if diffuse coronary atherosclerosis exists in the entering vessel, regardless of whether MLA is significant or not, FFR should be measured to determine the presence of stress-induced myocardial ischemia. Study limitations: First, the findings of this study were based on a single-center. Second, although intracoronary nitroglycerin was given before IVUS measurement, the possibility of catheter and guidewire induced spasm or bias cannot be excluded. Third, calculating the total plaque volume of conductive vessel by tracing all the IVUS pullback images was time-consuming and laborious. If the software for rapid automatic volumetric measurement is available, our study would be helpful in guiding the clinical decision process for equivocal cases, especially with anatomic and functional mismatch. Fourth, the results of this study would not be applicable for all types of coronary artery lesions. Validation of %TAV in the various types of lesions at various coronary artery sites is needed. Finally, although intravenous adenosine infusion has been known as standard method for inducing maximal coronary
hyperemia for FFR measurement, this study adopted intracoronary continuous adenosine infusion via microcatheter. It has been validated as a safe and effective method in inducing maximal hyperemia compared to standard intravenous infusion method [14]. 5. Conclusions Volumetric quantification of the atherosclerotic disease extent of the coronary artery, expressed as IVUS-derived %TAV, showed a strong correlation with FFR. Not only the segmental luminal narrowing but also the total plaque burden of conductive artery are major determinants for the presence of myocardial ischemia in intermediate stenosis of the LAD. Conflict of interest There is no conflict of interest. References [1] B. De Bruyne, F. Hersbach, N.H. Pijls, et al., Abnormal epicardial coronary resistance in patients with diffuse atherosclerosis but “normal” coronary angiography, Circulation 104 (2001) 2401–2406. [2] B.K. Koo, H.M. Yang, J.H. Doh, et al., Optimal intravascular ultrasound criteria and their accuracy for defining the functional significance of intermediate coronary stenosis of different locations, JACC Cardiovasc. Interv. 4 (2011) 803–811. [3] S.J. Kang, J.Y. Lee, J.M. Ahn, et al., Validation of intravascular ultrasound-derived parameters with fractional flow reserve for assessment of coronary stenosis severity, Circ. Cardiovasc. Interv. 4 (2011) 65–71. [4] I. Ben-Dor, R. Torquson, M.A. Gaglia Jr., et al., Correlation between fractional flow reserve and intravascular ultrasound lumen area in intermediate coronary artery stenosis, EuroIntervention 7 (2011) 225–233. [5] S.J. Kang, J.M. Ahn, H. Song, et al., Usefulness of minimal luminal coronary area determined by intravascular ultrasound to predict functional significance in stable and unstable angina pectoris, Am. J. Cardiol. 109 (2012) 947–953. [6] R. Waksman, J. Legutko, J. Singh, et al., FIRST: fractional flow reserve and intravascular ultrasound relationship study, J. Am. Coll. Cardiol. 61 (2013) 917–923. [7] V. Magni, A. Chieffo, A. Colombo, Evaluation of intermediate coronary stenosis with intravascular ultrasound and fractional flow reserve: its use and abuse, Catheter. Cardiovasc. Interv. 73 (2009) 441–448. [8] C.W. Nam, H.J. Yoon, Y.K. Cho, et al., Outcomes of percutaneous coronary intervention in intermediate coronary artery disease, JACC Cardiovasc. Interv. 3 (2010) 812–817. [9] G.S. Mintz, S.E. Nissen, W.D. Anderson, et al., American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS): A report of the American College of Cardiology Task Force on Clinical Expert consensus Documents, J. Am. Coll. Cardiol. 37 (2001) 1478–1492. [10] G.S. Mintz, J.A. Kovach, S.P. Javier, et al., Mechanisms of lumen enlargement after excimer laser coronary angioplasty: an intravascular ultrasound study, Circulation 92 (1995) 3408–3414. [11] N. Gonzalo, J. Escaned, F. Alfonso, et al., Morphometric assessment of coronary stenosis relevance with optical coherence tomography: a comparison with fractional flow reserve and intravascular ultrasound, J. Am. Coll. Cardiol. 59 (2012) 1080–1089. [12] S.J. Nicholls, I. Sipahi, P. Schoenhagen, et al., Intravascular ultrasound assessment of novel antiatherosclerotic therapies: rationale and design of the Acyl-CoA: cholesterol acyltransferase intravascular atherosclerosis treatment evaluation (ACTIV-ATE) study, Am. Heart J. 152 (2006) 67–74. [13] M. Yamagishi, H. Hosokawa, S. Saito, et al., Coronary disease morphology and distribution determined by quantitative angiography and intravascular ultrasound:
X.J. Jin et al. / International Journal of Cardiology 185 (2015) 56–61 re-evaluation in a cooperative multicenter intravascular ultrasound study (COMIUS), Jpn. Circ. J. 66 (2002) 735–740. [14] M.H. Yoon, S.J. Tahk, H.M. Yang, et al., Comparison of the intracoronary continuous infusion method using a microcatheter and the intravenous continuous adenosine infusion method for inducing maximal hyperemia for fractional flow reserve measurement, Am. Heart J. 157 (2009) 1050–1056. [15] S. Glagov, E. Weisenberg, C.K. Zarins, R. Stankunavicius, G.J. Koletitis, Compensatory enlargement of human atherosclerotic coronary arteries, N. Engl. J. Med. 316 (1987) 1371–1375.
61
[16] S.E. Nissen, J.C. Gurley, C.L. Grines, et al., Intravascular ultrasound assessment of lumen size and wall morphology in normal subjects and patients with coronary artery disease, Circulation 84 (1991) 1087–1099. [17] G.S. Mintz, J.A. Painter, A.D. Pichard, et al., Atherosclerosis in angiographically “normal” coronary artery reference segments: an intravascular ultrasound study with. Clinical correlations, J. Am. Coll. Cardiol. 25 (1995) 1479–1485.
