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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 5  |  Issue : 1  |  Page : 33-41

Diagnostic performance of coronary computed tomography angiography-derived instantaneous wave-free ratio for myocardial bridge


1 Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University; Department of Radiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
2 Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China

Date of Submission11-Feb-2020
Date of Acceptance11-Mar-2020
Date of Web Publication4-Apr-2020

Correspondence Address:
Dr. Chang Sheng Zhou
Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu
China
Prof. Long Jiang Zhang
Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, Jiangsu
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cp.cp_6_20

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  Abstract 


Purpose: The purpose of the study was to investigate the diagnostic performance of instantaneous wave-free ratio (iFR) based on coronary computed tomography (CT) angiography (CCTA) (iFRCT) for a myocardial bridge (MB). Materials and Methods: One hundred and fourteen patients with 115 MBs from 9 Chinese medical centers were prospectively included in this study. All patients underwent CCTA and subsequent invasive coronary angiography with fractional flow reserve (FFR). iFRCTs were measured at 2–4 cm distal to the lesions. Diagnostic performance of iFRCT was assessed using Bland–Altman analysis with invasive FFR as the reference in the entire sample, as well as in subgroups based on MB depth and length. Results: iFRCT has 0.90 sensitivity (95% confidence interval: 0.75–0.97), 0.73 specificity (0.62–0.83), and 0.79 accuracy (0.70–0.86) in the overall analysis. None of the three measures (sensitivity, specificity, and accuracy) differed significantly between superficial (≤2 mm) and deep MB, short (≤30 mm) and long MB, or low (<70% diameter occlusion) and high stenosis (P > 0.05 for all). However, positive predictive value was lower in the low stenosis (<70%) group (0.37 [0.20–0.58] vs. 0.90 [0.72–0.97] in the high stenosis group, P < 0.001). Negative predictive value, in contrast, was higher in the low stenosis group (0.98 [0.87–1.00] vs. 0.75 [0.43–0.93], P = 0.024). The Bland–Altman analysis showed a slight difference between iFRCT and invasive FFR (0.04 in the overall analysis and all subgroup analyses, with an exception of 0.05 in the long MB subgroup). Conclusion: iFRCT has a high diagnostic performance in detecting MB related lesion-specific ischemia.

Keywords: Coronary computed tomography angiography, fractional flow reserve, instantaneous wave-free ratio, myocardial bridge


How to cite this article:
Zhang XY, Zhou F, Tang CX, Xu PP, Zhou CS, Zhang LJ. Diagnostic performance of coronary computed tomography angiography-derived instantaneous wave-free ratio for myocardial bridge. Cardiol Plus 2020;5:33-41

How to cite this URL:
Zhang XY, Zhou F, Tang CX, Xu PP, Zhou CS, Zhang LJ. Diagnostic performance of coronary computed tomography angiography-derived instantaneous wave-free ratio for myocardial bridge. Cardiol Plus [serial online] 2020 [cited 2020 May 27];5:33-41. Available from: http://www.cardiologyplus.org/text.asp?2020/5/1/33/281942

* Drs. Xin Yu Zhang and Fan Zhou had equal contribution to this work.





  Introduction Top


Myocardial bridge (MB) is a common congenital abnormality of coronary artery course.[1] The incidence of MB is as high as 15%–80% based on the autopsy,[2] and 18%–58% based on coronary computed tomography (CT) angiography (CCTA).[3],[4],[5],[6] Most MB patients are asymptomatic, but some MB present with angina pectoris, acute coronary syndrome, and even sudden cardiac death.[7],[8],[9],[10],[11],[12] Thus, to classify these patients with potentially malignant MB is an important task.

CCTA is the golden standard in delineating anatomical features of MB (including milking effect, i.e., MB luminal stenosis at systole and then luminal normality at diastole) and associated atherosclerosis proximal to MB. Invasive fractional flow reserve (FFR) is the gold standard to assess the functional status of the coronary arteries [13] but is time consuming and requires the use of vasodilator. Instantaneous wave-free ratio (iFR) could be measured without administrating any vasodilator, and many studies showed that iFR is equally efficacious as FFR in demonstrating lesion-specific stenosis.[14],[15],[16],[17] Importantly, iFR is a diastolic specific indicator, whereas FFR measures the mean pressure of the systole and diastole.[18] Tarantini et al.[19] validated the feasibility of iFR for the physiological MB assessment in 20 patients compared with FFR.

iFR based on CCTA (iFRCT) is a noninvasive method to calculate iFR without additional CT examinations or radiation exposure and provides both anatomical and functional information simultaneously. Previous studies showed that iFRCT is useful in detecting lesion-specific ischemia.[20]

Based on its relevance to diastolic specific features, we speculated that iFRCT is appropriate to detect lesion-specific ischemia caused by MB and conducted a retrospective analysis to examine its diagnostic performance using invasive FFR as the reference.


  Materials and Methods Top


Study population

This study was approved by the local institutional review board and written informed patient consent was obtained. The data used in this study have been reported in our previous studies [21],[22] but with distinct purposes. Briefly, 394 patients with suspected or known coronary artery disease (CAD) were included from nine Chinese medical centers between May 1, 2015, and June 30, 2018. All patients underwent CCTA and subsequent invasive coronary angiography (ICA) with FFR of at least one coronary lesion. The interval between CCTA and ICA was no more than 3 months. For inclusion in the final analysis, patients must have MB and none of the following conditions: patients without MB (n=213); target vessel (MB) without invasive FFR (n=29); MB vessel with previous coronary artery stent implantation (n=3); previous coronary artery bypass grafting (n=0); complex congenital heart disease (n=0); missing or insufficient CCTA images (n=8); and inadequate for iFRCT calculation (n=27). The final analysis included 114 patients (one patient had 2 MBs). Patient selection is displayed in [Figure 1].
Figure 1: Flowchart of the study

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Coronary computed tomography angiography acquisition protocols

CCTA acquisition was performed using CT scanners with ≥64 detector rows (Somatom Definition/Flash/Force, Siemens Healthineers, Forchheim, Germany; or Aquilion One, Toshiba, Otawara, Japan) in each medical center. All patients received sublingual nitroglycerin (0.1 mg per dose, Nitroglycerin Inhaler; Jingwei Pharmacy Co., Ltd., Jinan, China) 3–5 min before CCTA acquisition. Beta-blockers were administered to regulate the heart rate if necessary. The specific scanning protocols were described in our previous study.[21] All patients received 60–65 mL of iodinated contrast agent (Ultravist 370 mg I/mL, Bayer, Schering Pharma, Berlin, Germany) by intravenous injection (4–5 mL/s), followed by 20–40 mL of saline with the same injection rate.

MB anatomical parameters measurement

MB is defined as the coronary artery segment surrounded by the myocardium on CCTA image. The measurement of the anatomical parameters of MB was performed on the postprocessing workstation (SyngoVia, Siemens Healthcare). The parameters measured included the location, length, depth of the MB on the axial image, and the curved planar reformation image at the diastolic CCTA by an experienced imaging physician. As shown in [Figure 2], the distance from the coronary artery ostium to the entrance of the MB is regarded as the location of MB, and the distance from the entrance to the exit of the bridge is regarded as the length of MB. The depth of MB is defined as the maximum thickness of the myocardium covering the surface of the coronary artery. A depth of 1 mm is recorded when the overlying myocardium is ≤1 mm for the subsequent analysis. Similar to our previous study, patients with MB are divided into superficial MB (≤2 mm) group and deep MB group (>2 mm) according to the depth, as well as short MB group (≤30 mm) and long MB group (>30 mm) according to the length.[22]
Figure 2: MB anatomical features measurement on coronary computed tomography angiography. (a) Axial computed tomography image showing the measurement method of MB depth, the depth of MB is 1.6 mm. (b and c) Curved planar reformation images showing the measurement method of the position and length of MB, the position and length of MB are 18.8 mm and 62.4 mm, respectively

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Calculation of instantaneous wave-free ratio based on computed tomography angiography

iFRCT calculations are performed using a dedicated software research prototype (uCT-FFR version 1.5, United-Imaging Healthcare, Shanghai, China). Based on CCTA images and the method of computational fluid dynamics, the software enables to create a patient-specific model of the coronary artery tree and calculate the iFRCT noninvasive. First, the anatomical model was generated by an automatic approach, resulting in a three-dimensional mesh representing the coronary artery tree. To determine the inlet boundary condition, a waveform pressure was coupled to simulate the physiological condition. As for the outlet boundary condition, a method based on transluminal attenuation gradient and total resting blood flow was used to determine the microcirculatory of each branch. The computation of iFRCT was based on solving the Navier–Stokes equations, the physical laws that govern fluid dynamics. Blood was treated as an incompressible, viscous Newtonian fluid (ρ = 1056 kg/m 3, μ = 0.0035 Pa.s), and the vessel wall was assumed to be rigid. For any vertex in the coronary tree, iFRCT was generated by computing the pressure ratio. The previous study has described the calculation principle of this software in detail.[21] iFRCT values were determined for coronary arteries ≥2 mm in diameter by one observer at 2–4 cm of the lesions at the target blood vessels. The observer was blinded to the invasive FFR results. Lesions with iFRCT ≤0.89 indicated lesion-specific ischemia.[23]

Invasive coronary angiography and fractional flow reserve measurements

ICA and FFR were performed by experienced invasive cardiologists in each medical center according to the standard procedures, which have been previously described.[21] The diameter stenosis caused by a proximal atherosclerotic plaque of MB was visually recorded during ICA. The luminal stenosis ≥70% was regarded as hemodynamical significance. FFR ≤0.80 was defined as lesion-specific ischemia.[24],[25],[26]

Statistical analysis

Statistical analysis was conducted using SPSS V.23 (SPSS, Chicago, Illinois, USA) and Medcalc (MedCalc; version 17.6). The Kolmogorov–Smirnov test was conducted to assess the normality of continuous variables. Continuous variables were expressed as mean ± standard deviation if normally distributed and median and interquartile range otherwise. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) and the area under the curve (AUC) derived from receiver operating characteristics analysis were calculated for iFRCT in the overall analysis that included all patients, as well as subgroups based on MB depth/length as well as the degree of stenosis using invasive FFR as the reference. The Bland–Altman analysis was used to analyze the agreement between iFRCT and invasive FFR. The Chi-square test was used to compare diagnostic performance between different groups. DeLong test [27] was used to compare the AUCs. P < 0.05 is considered to be statistically significant.


  Results Top


Patient characteristics

A total of 114 patients (60.9 ± 8.8 years of age, 72.8% men) with 115 MBs and proximal atherosclerotic plaques (60% [55%–70%] diameter stenosis) were included in the analysis [Table 1]. No plaque was found in the tunneled and distal segments of MB. Most MBs located in the left anterior descending (LAD) (112 [97.4%]), except 2 in the right coronary artery (RCA) and 1 in the left circumflex. One patient had two MBs, located in LAD and RCA, respectively. Of the 115 MBs, 104 MBs (90.4% [104/115]) were superficial and 61 MBs (53.0% [61/115]) were short. According to the record of ICA, 41 (35.7% [41/115]) MB vessels showed ≥70% occlusion. The prevalence of ischemia-specific vessels was 40 (34.8% [40/115]) according to the FFR results, corresponding to 56 (48.7% [56/115]) according to the iFRCT results.
Table 1: The demographics and myocardial bridge features of all patients

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Diagnostic performance of instantaneous wave-free ratio based on computed tomography angiography

The diagnostic performances of iFRCT for detecting ischemic-specific lesions are shown in [Table 2]. The sensitivity, specificity, accuracy, PPV, and NPV of iFRCT for detecting ischemic-specific lesions were 0.90 (0.75–0.97), 0.73 (0.62–0.83), 0.79 (0.70–0.86), 0.64 (0.50–0.76), and 0.93 (0.83–0.98) in all MB vessels, respectively. No significant differences were found in the sensitivity (P > 0.999), specificity (P=0.756), accuracy (P=0.848), PPV (P=0.747), and NPV (P > 0.999) between the superficial and deep MB groups. There were no significant differences in sensitivity (P=0.114), specificity (P=0.311), accuracy (P=0.086), NPV (P=0.449), and PPV (P=0.083) between the short and long MB groups. High stenosis group (≥70%) showed higher PPV (0.90 [0.72–0.97] vs. 0.37 [0.20–0.58], P < 0.001) and lower NPV (0.75 0.43–0.93] vs. 0.98 [0.87–1.00], P = 0.024) than low stenosis group (<70%). The AUC in the deep MB group was markedly higher than that in the superficial MB group (1.00 [0.72–1.00] vs. 0.80 [0.71–0.87), P <0.001). The AUC did not differ in subgroups with different degree of stenosis (P = 0.359) [Table 2] and [Figure 3]. [Figure 4] shows representative cases. [Table 3] shows the detailed information of 24 mismatch cases between iFRCT and invasive FFR. Of the mismatched cases, 20 cases were false positive and 4 cases were false negative. Eighteen (75% [18/24]) cases had atherosclerotic plaques proximal to MB, showing <70% diameter stenosis. Fifteen cases (62.5% [15/24]) were long MBs and 21 cases (87.5% [21/24]) were superficial MB. iFRCT in 20 cases (83.3% [20/24]) ranged from 0.75–0.91. The degree of stenosis caused by proximal atherosclerotic plaques of MB showed no significant difference between mismatched cases and matched cases (60% [55%–68.7%] vs. 65% [55%–70%], P = 0.107).
Table 2: Diagnostic performance of Instantaneous wave-free ratio based on computed tomography angiography for lesion-specific ischemia of myocardial bridge

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Figure 3: Receiver operating characteristics curve for diagnostic performance at different groups. (a) All MB vessels, (b) Superficial MB group, (c) Deep MB group, (d) Short MB group, and (e) Long MB group

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Figure 4: Instantaneous wave-free ratio based on computed tomography angiography and invasive fractional flow reserve of patients with MB. (a-c) A 61-year-old male with MB in the mid-segment of the left anterior descending and proximal atherosclerotic plaques (70% diameter stenosis). Positive instantaneous wave-free ratio based on computed tomography angiography value (0.70) and invasive fractional flow reserve value (0.78) 2–4 cm distal to the lesion were observed. (d-f). A 74-year-old male with MB in the mid-segment of the left anterior descending and proximal atherosclerotic plaques (60% diameter stenosis). Negative instantaneous wave-free ratio based on computed tomography angiography value (0.95) and invasive fractional flow reserve value (0.89) 2–4 cm distal to the lesion were observed

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Table 3: The information of mismatch cases

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Relationship between instantaneous wave-free ratio based on computed tomography angiography and invasive fractional flow reserve

The Bland–Altman analysis showed a slight difference between iFRCT and invasive FFR (0.04 in the overall analysis and all subgroups, with the exception of 0.05 in long MB group) [Figure 5].
Figure 5: Bland–Altman plots of instantaneous wave-free ratio based on computed tomography angiography and invasive fractional flow reserve. (a) All MB vessels, (b) Superficial MB group, (c) Deep MB group, (d) Short MB group, and (e) Long MB group

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  Discussion Top


The results from the current study showed reasonable performance of iFRCT in assessing MB. Using the invasive FFR as reference, iFRCT had 0.90 sensitivity (95% confidence interval: 0.75–0.97), 0.73 specificity (0.62–0.83), and 0.79 accuracy (0.70–0.86).

Based on our preliminary literature search, iFRCT has been used to investigate lesion-specific ischemia in CAD patients in two previous studies, with reported accuracy, sensitivity, and specificity at 0.75–0.79, 0.71–0.85, and 0.69–0.83, respectively.[20],[28] In the current study, the accuracy, sensitivity, and specificity of iFRCT for diagnosing MB-related ischemia were 0.79, 0.90, and 0.73, respectively. Despite the moderate PPV in the long MB group, deep MB group, and <70% stenosis group (0.59, 0.50, and 0.37, respectively), the results obtained from iFRCT are fairly consistent with that obtained with invasive FFR, with a mean difference of 0.05 in the long MB group and 0.04 in the deep MB group. Previous studies have also shown that CT-FFR could significantly improve specificity and PPV, whereas iFRCT trends to increase the sensitivity and NPV, suggesting that iFRCT could be a useful gatekeeper for ICA and FFR examinations.[20],[29],[30] Given that MB contraction may cause a negative systolic pressure difference (the distal pressure is higher than the proximal pressure), resulting in a mean pressure significantly higher than the diastolic pressure. The lower PPVs in these groups could be reasonably attributed to underestimated hemodynamic abnormalities since the mean pressure over the complete cardiac cycle is used in invasive FFR. In Ge et al.'s study,[31] 88% (61/69) of the patients had atherosclerotic involvement of the segment proximal to MB, which, in turn, could exacerbate myocardial ischemia. They also found an apparent higher degree of coronary flow velocity reserve impairment in patients with more severe stenosis. In our opinion, the nature of invasive FFR and the impact of CAD proximal to MB resulted in the lower PPV and higher NPV in the low stenosis group (<70%) than those in the high stenosis group in the current study. van de Hoef et al.[32] explored the diagnostic accuracy of iFR and FFR for stenosis-specific myocardial ischemia and found similar discordance between FFR and iFR to the present study (19% vs. 21%). Similar to these findings, our previous study showed good diagnostic performance of CT-FFR in identifying lesion-specific ischemia in patients with MB, with a 0.96 specificity.[22] In the present study, iFRCT had 0.90 sensitivity and 0.93 NPV. Taken together, iFRCT has promising potential in patients with MB.

To further investigate the factors affecting the diagnostic performance of iFRCT, we conducted a subgroup analysis based on the MB depth/length. A comparison of diagnostic measures of iFRCT in these subgroups did not show statistically significant differences, but the diagnostic performance in the short MB group showed a trend for higher sensitivity (1.00 vs. 0.80), specificity (0.78 vs. 0.68), accuracy (0.85 vs. 0.72), PPV (0.69 vs. 0.59) as well as NPV (1.00 vs. 0.85). Of note, most of the mismatched cases were in the long MB group, indicating that iFRCT is particularly useful in assessing lesion-specific ischemia in patients with short MB. FFR was 0.75–0.80 in all (4/4) false-negative cases in the mismatched group, suggesting that this gray zone (0.75–0.80) could have affected the diagnostic accuracy of iFRCT and contributed to the false-negatives. In 85% (17/20) of false-positive cases, iFRCT was between 0.75 and 0.89, again suggesting a gray zone of iFRCT in diagnosing lesions-specific ischemia.

The current study has some limitations. First, we used invasive FFR (cutoff value ≤0.80) rather than invasive iFR (cutoff value ≤0.89) as the reference standard for pragmatic reasons. Second, the sample size was small. In particular, the deep MB group had only 11 cases. Prospective multicenter studies with a large sample size using invasive iFR as the reference are needed to verify the preliminary results from the current study. Third, the iFRCT software modeling calculation used in this study is complex and time consuming and requires further development before eventual use in daily practice. Fourth, the intraobserver and interobserver consistent was not analyzed in this study.


  Conclusion Top


The current study shows that iFRCT has good diagnostic performance for detecting functional ischemia in patients with MB. Further studies are needed to examine the clinical relevance of iFRCT in patients with MB.

Financial support and sponsorship

This study was financially supported by the National Key Research and Development Program of China (2017YFC0113400 for L.J.Z.) and Key Program of the National Natural Science Foundation of China (No. 81830057 for L.J.Z.).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

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