Diagnostic Performance of Angiography-Based Fracti
Diagnostic Performance of Angiography-Based Fracti
Diagnostic Performance of
Angiography-Based Fractional Flow
Reserve for Functional Evaluation of
Coronary Artery Stenosis
Changling Li 1 , Xiaochang Leng 2 , Jingsong He 2 , Yongqing Xia 2 , Wenbing Jiang 3 ,
Yibin Pan 4 , Liang Dong 1 , Yong Sun 1 , Xinyang Hu 1 , Jian’an Wang 1 , Jianping Xiang 2* and
Jun Jiang 1*
1
Department of Cardiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China,
2
ArteryFlow Technology Co., Ltd., Hangzhou, China, 3 Department of Cardiology, The Third Clinical Institute Affiliated to
Wenzhou Medical University, Wenzhou, China, 4 Department of Cardiology, Affiliated Jinhua Hospital, Zhejiang University
School of Medicine, Jinhua, China
Edited by: Background: A new method for calculating fraction flow reserve (FFR) without pressure-
Sebastian Kelle,
wire (angiography-derived FFR) based on invasive coronary angiography (ICA) images
Deutsches Herzzentrum
Berlin, Germany can be used to evaluate the functional problems of coronary stenosis.
Reviewed by: Objective: The aim of this study was to assess the diagnostic performance of a
Jan Brüning,
Charité—Universitätsmedizin
novel method of calculating the FFR compared to wire-based FFR using retrospectively
Berlin, Germany collected data from patients with stable angina.
Haikun Qi,
ShanghaiTech University, China Methods: Three hundred patients with stable angina pectoris who underwent ICA
Masafumi Ono, and FFR measurement were included in this study. Two ICA images with projections
Cardialysis, Netherlands
>25◦ apart at the end-diastolic frame were selected for 3D reconstruction. Then, the
*Correspondence:
Jun Jiang
contrast frame count was performed in an angiographic run to calculate the flow velocity.
[email protected] Based on the segmented vessel, calculated velocity, and aortic pressure, AccuFFRangio
Jianping Xiang
distribution was calculated through the pressure drop equation.
[email protected]
Results: Using FFR ≤ 0.8 as a reference, we evaluated AccuFFRangio performance for
Specialty section: 300 patients with its accuracy, sensitivity, specificity, positive predictive value (PPV), and
This article was submitted to
Cardiovascular Imaging,
negative predictive value (NPV). Comparison of AccuFFRangio with wire-measured FFR
a section of the journal resulted in an area under the curve (AUC) of 0.954 (per-vessel, p < 0.0001). Accuracy for
Frontiers in Cardiovascular Medicine
AccuFFRangio was 93.7% for Pa set from measurement and 87% for Pa = 100 mmHg
Received: 24 May 2021
in this clinical study. Overall sensitivity, specificity, PPV, and NPV for per-vessel were 90,
Accepted: 15 September 2021
Published: 12 October 2021 95, 86.7, 96.3, and 57.5, 97.7, 90.2, 86.3%, respectively. Overall accuracy, sensitivity,
Citation: specificity, PPV, and NPV for 2-dimensional (2D) quantitative coronary angiography (QCA)
Li C, Leng X, He J, Xia Y, Jiang W, were 63.3, 42.5, 70.9, 34.7, and 77.2%, respectively. The average processing time of
Pan Y, Dong L, Sun Y, Hu X, Wang J,
Xiang J and Jiang J (2021) Diagnostic
AccuFFRangio was 4.30 ± 1.87 min.
Performance of Angiography-Based Conclusions: AccuFFRangio computed from coronary ICA images can be an accurate
Fractional Flow Reserve for Functional
Evaluation of Coronary Artery and time-efficient computational tool for detecting lesion-specific ischemia of coronary
Stenosis. artery stenosis.
Front. Cardiovasc. Med. 8:714077.
doi: 10.3389/fcvm.2021.714077 Keywords: fractional flow reserve, invasive coronary angiography, coronary artery, ischemia, stenosis
FIGURE 1 | AccuFFRangio analysis of intermediate stenosis of a left anterior descending artery (LAD). (a,b) Coronary angiography images from two different angles of
view. (c) The above chart shows the change of lumen diameter (red) along LAD with the computed reference diameter (green); the chart below shows the diameter
stenosis (red) and AccuFFRangio pullback (green). (d) Computed AccuFFRangio distribution; the AccuFFRangio value was 0.86. (e) The FFR measured by pressure
wire was 0.85.
>25◦ apart at the end-diastolic frame were selected for Contrast flow rate velocity for FFR computation was derived
three-dimensional (3D) reconstruction (6, 7, 11). To simplify from the TIMI frame counting method for the segmented
the geometry calibration procedure and achieve a reliable vessel. With the calculated velocity and input aortic pressure
correspondence in centerline points for 3D reconstruction, we from the measurement of the pressure at the coronary
have implemented three pairs of reference points to eliminate ostium, AccuFFRangio distribution can be calculated (Figure 1).
the isocenter offset and rotational angle parameter errors. Since AccuFFRangio value was taken at the same position of wire-
the pressure drop has a positive relationship with the coronary based FFR using angiography images as a reference. To
vessel flow rate, the frame count method is a relatively feasible compare the diagnostic accuracy of AccuFFRangio by using
solution (12). This method hypothesizes that the blood flow a fixed value of aortic pressure and to study the influence
velocity is proportional to the vessel cross-section diameter of fixed value on the performance of our approach in case
dimension. Typically, the pressure drop from proximal to distal some patient-specific pressures cannot be obtained, Pa =
stenosis is caused by two factors. The first is the viscous pressure 100 mmHg was set for each calculation of angio-based FFR
drop associated with friction. The second is the expansion (13, 14).
pressure drop due to the rapid change in radius, which is
usually characterized by narrowing. Pressure drop PR is related Statistical Analysis
to viscosity loss coefficient CVis , expansion loss coefficient Continuous variables with normally distributed were expressed
CExpan , and flow rate Q: PR = (CVis + CExpan • Q) • Q. More as mean ± standard deviation (SD) and non-normal distributed
detail of the derived equations can be seen in our previous variables as the median. Categorical variables were expressed as
study (11). percentages and data were analyzed on a per vessel basis. Pearson
correlation was used to quantify the correlation between FFR TABLE 1 | Baseline patient characteristics (n = 300).
and AccuFFRangio. Agreement between FFR and AccuFFRangio
Age, y 64.1 ± 9.6
was assessed on the Bland-Altman plot. Using FFR ≤ 0.8 as
Male 67% (201)
the reference standard, the performance of AccuFFRangio for
Weight (kg) 68.5 ± 34.5
predicting functionally significant stenosis was evaluated by
Height (cm) 165 ± 7.3
diagnostic accuracy, sensitivity, specificity, positive predictive
BMI, kg/m2 25.2 ± 13.9
value (PPV), and negative predictive value (NPV). The area
Systolic blood pressure (mm Hg) 130 ± 20
under the curve (AUC) of receiver operating characteristic
Diastolic blood pressure (mm Hg) 78 ± 15
(ROC) analysis was used to assess the diagnostic accuracy of
AccuFFRangio. All the statistical analyses were performed by Diabetes 21% (64)
RESULTS
Patient Characteristics TABLE 2 | Vessel characteristics (n = 300).
Figure 2 presents the study enrollment flow chart. Three
hundred eighteen patients with 318 vessels were included in Vessels
this clinical study from May 2016 to July 2019. Due to the LAD 61.7% (185)
incomplete data from six patients, 312 patients underwent ICA LCX 7.3% (22)
procedure and wire-FFR waveform analysis. Among them, 12 RCA 29.7% (89)
patients were excluded due to predefined exclusion criteria, Anatomy
including undocumented wire-position, poor image quality, Diameter stenosis, % 44 ± 12%
excessive vessel overlap, insufficient contrast, projections <25 <50% 67.3% (202)
degrees, excessive pressure wire drift, and left main coronary ≥50% 32.7% (98)
artery lesions. In the end, 300 patients with 300 vessels were Physiology
included in the final analysis. FFR (per vessel) 0.84 ± 0.10
Mean FFR was 0.84 ± 0.10, as shown in Figure 3, and mean Vessels with FFR ≤ 0.8 26.7% (80)
percentage diameter stenosis (%DS) form 2D-QCA was 44 ± Vessels with FFR > 0.8 73.3% (220)
12%. FFR ≤ 0.80 was found in 80 (26.7%) vessels and the mean Diffuse or serial lesions 32.3% (97)
contrast flow rate velocity was 0.17 ± 0.05 m/s. Baseline patient Bifurcation lesions 2.7% (8)
and procedural characteristics are listed in Tables 1, 2. Calcified lesions 2% (6)
Myocardial bridge 5.7% (17)
Correlation and Agreement Between
AccuFFRangio and FFR
Good correlations were observed in Figure 4 with a correlation
coefficient of r = 0.83 (p < 0.001). There were good agreements
In addition, the mean processing time of AccuFFRangio
between AccuFFRangio and FFR in the Bland-Altman plot with
assessment was 4.30 ± 1.87 min including the 3D anatomic
a mean difference value of −0.001 (limits of agreement: −0.124
model reconstruction and AccuFFRangio calculation for
to 0.122) when Pa measured at the coronary ostium and −0.030
each patient.
(limits of agreement: −0.155 to 0.095) when Pa = 100 mmHg
was used, as shown in Figure 5. The number of patients with the
absolute difference between AccuFFRangio and FFR falling out of
the 95% CI was 9 (3%) when Pa was set according to the patients DISCUSSION
and 18 (6%) when Pa was set equal to a fixed value.
Wire-based FFR has potential risks in measurement procedures
Diagnostic Performance of AccuFFRangio and vasodilator complications, and the complexity of the
and 2D-QCA operation is also a challenge. In this situation, this study had
Accuracy for AccuFFRangio was 93.7% in this clinical study. demonstrated a reliable and efficient computational method
Overall sensitivity, specificity, PPV, and NPV were 90, 95, 86.7, AccuFFRangio for the functional evaluation of lesion-specific
and 96.3%, respectively (Table 3). Meanwhile, these values for ischemia of coronary artery stenosis based on ICA images
AccuFFRangio, when Pa = 100 mmHg was implemented in the without injecting vasodilators. Thus, instead of using invasive
calculation, were 87, 57.5, 97.7, 90.2, and 86.3%. Comparison of wire-based FFR for evaluating the severity of suspected coronary
AccuFFRangio and 2D-QCA with pressure wire measured FFR as heart disease, AccuFFRangio uses a combination of the 3D
reference resulted in an AUC for AccuFFRangio of 0.954 (95%CI: structure of the coronary vessel and computational fluid
0.924–0.975) and 0.934 (95%CI: 0.900–0.960, when Pa = 100 dynamics (CFD)-based equations on account of TIMI frame
mmHg) and 2D-QCA of 0.567 (95% CI: 0.509–0.624), as shown count to analyze the functional performance in a short time
in Figure 6. of 5 min. The diagnostic accuracy of AccuFFRangio was 93.7%
FIGURE 4 | Correlation between AccuFFRangio computation and conventional pressure wired measured FFR. (A) Pa from the measurement of the pressure at the
coronary ostium; (B) Pa set as equal to 100 mmHg.
FIGURE 5 | Agreement between AccuFFRangio computation and conventional pressure wired measured FFR. (A) Pa from the measurement of the pressure at the
coronary ostium; (B) Pa set as equal to 100 mmHg.
compared to pressure wire-derived FFR, which shows a higher coronary tree construction based on the geometry of two
accuracy compared to 2D-QCA with an accuracy of 63.3%. or more projections with a minimum separation of 30◦
For assessment of FFR without pressure-wire, many and application of an automatic resistance-based lumped
research groups have made significant efforts and developed model of the entire coronary tree, FFRangio (17–19) showed a
different angiography-based FFR methods. Morris et al. high concordance between pressure-wire measured FFR. By
(15) described that the construction of arteries was based reconstructing a 3D QCA model of the target vessel using two
on two projections from similar phases of the cardiac cycle angiographic projections recorded at least 25◦ intervals, the
with good vessel opacification and contrast. Meanwhile, QFR was computed through mathematic equations incorporated
the virtual FFR was calculated from CFD simulations with with contrast flow velocity determined using frame count
generic downstream boundary conditions applied to the analysis (6, 20). It represented a high diagnostic accuracy
arterial outlet with a Windkessel model (16). With a 3D with FFR, reducing the number of patients for pressure-wire
AccuFFRangio ≤ 0.8 AccuFFRangio ≤ 0.8 (Pa = 100 mmHg) Diameter stenosis by QCA ≥ 50%
measurements. In the current study of AccuFFRangio, the The accuracy of AccuFFRangio in the present study was 93.7%
3D geometry model construction and calculation of FFR for per-vessel bias, which is comparable to the clinical trials
were different from the methods described above. We used with patients over 200, such as 83% for WIFI II Study (21),
three physiological points to do the vessel calibration to 86.8% for FAVOR II Europe-Japan Study (7), 92.7% for FAVOR
eliminate the error during the reprojection procedure, as the II China Study (4), and 93.5% for FAST-FFR Study (18). The
same processes in our previous studies (11). Moreover, the sensitivity, specificity, and AUC for the four clinical trials were
velocity of the inlet of the blood vessel was set according to 86, 77%, and 0.86 for WIFI II Study (21), 86.5, 86.9%, and 0.92
the TIMI frame count. The blood pressure at the aorta was for FAVOR II Europe-Japan Study (7), 94.6, 91.7%, and 0.96
chosen equal to the value from measuring the pressure at the for FAVOR II China Study (4), and 91.2, 92.2%, and 0.944 for
coronary ostium. FAST-FFR Study (18). Those for AccuFFRangio were 90, 95%,
and 0.954. Compared to Pa taken from the measurement at the 93.7, 90, and 95%, respectively. Those were better than the
coronary ostium, as Pa set equal to a fixed value of 100 mmHg, diagnostic performance of AccuFFRangio calculated based on Pa
the diagnostic performance decreased to 87% for accuracy setting equal to 100 mmHg. AccuFFRangio bears the potential
and 57.5% for sensitivity, respectively. Angiography-based FFR of improving angiography-based identification of functionally
can improve the low sensitivity of 2D-QCA in evaluating significant stenosis during coronary angiography procedure.
hemodynamically significant of coronary stenosis, from about
42.5–62.5–86.5–94.6% (4, 7, 21–23). Similarly, this method will Impact on Daily Practice
also increase the specificity from the original 58.1–76.5–86.9– AccuFFRangio can quickly and accurately calculate FFR values
92.2% (4, 7, 21–23). Thus, the implementation of angiography- based on coronary angiography images and can be used for
based FFR can avoid unnecessary revascularization of many functional assessment of patients with coronary heart disease,
interrogated vessels when performed coronary angiography. It is avoiding unnecessary PCI treatment.
also useful to optimize the strategies of percutaneous coronary
intervention (PCI) to reduce the number of the implanted stents
and improve the clinical outcome for patients who plan to DATA AVAILABILITY STATEMENT
perform PCI.
The time for calculating angiography-based FFR is also The original contributions presented in the study are included
essential for evaluating superiority when there is only limited in the article/supplementary material, further inquiries can be
time during the PCI operation. For vFFR (15), it took ∼ directed to the corresponding authors.
24 h for the CFD simulation of one case, which cannot be
implemented in the condition during PCI performance. Another ETHICS STATEMENT
method FFRangio took nearly 10 min for the whole procedure,
including reconstruction of the 3D geometry model of the entire The studies involving human participants were reviewed and
coronary tree and calculation of the FFR values based on lumped approved by Department of Cardiology, Second Affiliated
model (17, 18, 24, 25). But, it only took 4.3 ± 3.4 min to Hospital of Zhejiang University School of Medicine. Written
perform an analysis for one lesion (24). By constructing the informed consent for participation was not required for this
3D geometry model for only the target vessel and CFD-based study in accordance with the national legislation and the
equations on account of TIMI frame count to calculate the institutional requirements.
FFR values, the entire procedure was completed in a short time
of 5 min 59 s on average (6), which can be used during the
PCI operation. In addition, the entire process of calculating AUTHOR CONTRIBUTIONS
FFR with a similar algorithm used in this paper took about
CL and XL: concept and design of the study, analysis of the
5 min, which met the requirement of clinical application in
data, and drafting of the manuscript. JH: case calculation and
PCI surgery.
drafting of the manuscript. CL, LD, and XH: image annotation
It is worth noting the limitations of this clinical study.
of ICA and critical review of the manuscript. YX and JH:
Firstly, this was a retrospective study at one single center.
implementation of the algorithm and drafting of the manuscript.
Secondly, the study may have selection bias because of
JW and JX: conception and design of the study, analysis of
the relatively small number of positive cases (80 vessels,
the data, drafting of the manuscript, and final approval of the
26.7%) compared with the negative ones (220 vessels, 73.3%).
manuscript submitted. WJ, YP, YS, and JJ: have contributed to
Third, this study was an observational study. In the future,
the submitted work. All authors contributed to the article and
prospective, multi-center, and follow-up studies will be
approved the submitted version.
performed in the post-market clinical researches. Fourth,
abnormal pressure curves such as wave form distortion or
ventricularization were not found in this study due to the FUNDING
nature of our study population, while this could influence
the measurement of FFR; thus, further assessment should This work was supported by the National Natural Science
be considered. Foundation of China (Nos. 82170332, 81320108003, 31371498,
81100141, and 81570322), Zhejiang Provincial Public
CONCLUSIONS Welfare Technology Research Project (No. LGF20H020012),
Zhejiang Provincial key research and development plan
This clinical study demonstrates that AccuFFRangio is clinically (No. 2020C03016), the Major projects in Wenzhou of China
feasible. The performance is superior to angiographic assessment (No. 2019ZG0107), the Major projects in Jinhua of China
by 2D-QCA for evaluating coronary artery stenosis when (No. 2020A31003), Scientific research project of Zhejiang
using FFR as a reference. The accuracy, sensitivity, and Education Department (No. Y201330290), and Major medical
specificity of AccuFFRangio in identifying hemodynamically and health science and technology plan of Zhejiang Province
significant of coronary stenosis using 300 patient data were (No. WKJ-ZJ-1913).