- Academic Editors
†These authors contributed equally.
Background: Coronary biomechanical stress contributes to the plaque
rupture and subsequent events. This study aimed to investigate the impact of
plaque biomechanical stability on the physiological progression of intermediate
lesions, as assessed by the radial wall strain (RWS) derived from coronary
angiography. Methods: Patients with at least one medically treated
intermediate lesion at baseline who underwent follow-up coronary angiography over
6 months were included. The maximal RWS (RWS
Recent advances in coronary plaque imaging have led to an increased interest in detecting and treating of vulnerable plaque features that are associated with the risk of future cardiovascular events. A vulnerable coronary plaque is typically characterized by a thin fibrous cap and large lipid core with abundant inflammatory cells, which can be visualized using non-invasive or invasive coronary imaging modalities [1]. Although a number of imaging studies have provided important insights by showing that the geometrical and morphological features of vulnerable plaques are of clinical significance (i.e., associated with lesion progression and clinical outcomes), their relatively low positive predictive value for patient prognosis indicates additional information is needed to extend our knowledge of the “high-risk” plaques [2, 3]. In this context, coronary strain, which can be measured using intravascular elastography or palpography, has been proposed as a valuable biomechanical method to assess the plaque vulnerability [4, 5]. High-strain spots across the coronary lesions have been proven to correlate with an increased risk of acute coronary syndrome [5]. However, the conventional method of strain analysis is cumbersome, which hinders the adoption of biomechanical assessment in clinical practice. To address this unmet need, Hong et al. [6] introduced a simplified artificial intelligence-aided method of calculating coronary strain, labelled as radial wall strain (RWS), from conventional coronary angiography (CAG). They also demonstrated that angiography-derived RWS correlates well with the validated characteristics of vulnerable plaques by optical coherence tomography (OCT), indicating that RWS could be a less-invasive alternative tool for evaluating plaque vulnerability from a biomechanical aspect.
Plaque progression, usually measured by the serial change in the severity of luminal stenosis on angiography or atheroma volume on intracoronary imaging, has been acknowledged as a necessary and modifiable step between early atherosclerosis and acute coronary events [7]. Beyond the anatomic parameters, coronary physiology is also an important aspect of plaque characteristics, which has independent significance on clinical outcomes [8]. In particular, recent studies have revealed that pressure wire-based or angiography-derived physiological indices could be a surrogate marker for evaluating the functional change of coronary lesions, and for monitoring the effectiveness of a certain anti-atherosclerotic therapy [9, 10, 11].
The present study aimed to investigate the association between the biomechanical stability of coronary plaques as assessed by angiographic RWS and disease progression in coronary physiology as evaluated by serial quantitative flow ratio (QFR).
This retrospective cohort study was performed at Tongji Hospital, Tongji
University, Shanghai. Patients with suspended or known coronary artery disease
(CAD) who underwent serial CAG examinations at intervals of
Study flow chart. CAD, coronary artery disease; CABG, coronary artery bypass graft; MACE, major adverse cardiac events; CAG, coronary angiography; AMI, acute myocardial infarction.
Angiographic images were obtained according to the standard of care based on
local practice. The decision to perform percutaneous coronary intervention (PCI)
during the procedure was at the discretion of the treating physician. Serial
Murray-law based QFR and quantitative coronary angiography (QCA) analyses were
performed at index and follow-up CAG procedures using a QFR system software
(AngioPlus Core version 2.0, Pulse Medical, Shanghai, China), as previously
described [12]. QFR and QCA data including minimum lumen diameter, reference
diameter, lesion length, and percent diameter stenosis (DS%) were routinely
obtained from the software. In addition to the computation of the traditional QFR
value of the entire vessel, we measured the absolute change in QFR across the
interrogated lesion (named as lesion-specific
Offline RWS was measured using a recently developed software (AngioPlus Core
version 3.0, Pulse Medical, Shanghai, China) by experienced analysts who were
blinded to the serial QFR results. The detailed theory and procedures for RWS
analysis have been described and validated by previous studies, and RWS is
defined as the relative diameter deformation over the cardiac cycle for each
position [6, 13]. In brief, one high-quality angiographic projection at the
end-diastole was selected and transferred to software by the analyst. Another 3
frames at different periods of the cardiac cycle were automatically selected by
the software. Subsequently, the lumen contours of the interrogated vessels were
automatically delineated in the four selected frames and thus depicting a map of
the lumen diameters along the interrogated segments throughout the cardiac cycle.
In the present study, the RWS was calculated along the interrogated lesions, and
the maximum RWS (RWS
All clinical data during the baseline procedure, including patient demographics,
clinical presentation, conventional risk factors, blood tests, and medical
treatments, were collected by reviewing the hospital database. Diabetes mellitus
was defined as glycosylated hemoglobin
Categorical variables are expressed as absolute counts and percentages
and compared between the groups using Pearson’s chi-square or Fisher’s exact
test. Continuous variables are presented as mean
A total of 175 intermediate de novo lesions from 156 patients who underwent
serial angiography were enrolled in the present study. Follow-up CAG measurements
were performed at a median time interval of 12.4 (10.9, 16.6) months, after the
index procedures. The baseline patient characteristics are shown in Table 1. The
mean age was 65.2
Patient characteristics (N = 156) | ||
Follow-up period, months | 12.4 (10.9, 16.6) | |
Age, years | 65.2 | |
Male (%) | 108 (69.2) | |
Body mass index, kg/m |
24.3 | |
Hypertension (%) | 105 (67.3) | |
Diabetes mellitus (%) | 63 (40.4) | |
Hyperlipidemia (%) | 104 (66.7) | |
Previous or current smoker (%) | 87 (55.8) | |
Previous myocardial infarction (%) | 23 (14.7) | |
Previous stroke | 13 (8.3) | |
Clinical presentation | ||
Stable coronary artery disease (%) | 95 (60.9) | |
Acute coronary syndrome |
61 (39.1) | |
Medical treatments at discharge | ||
Statins (%) | 152 (97.4) | |
107 (68.6) | ||
ACEI or ARB (%) | 96 (61.5) | |
Dual antiplatelet therapy (%) | 106 (67.9) | |
Laboratory data | ||
high sensitivity C-reactive protein, mg/L | 2.12 (0.81, 4.75) | |
Estimated glomerular filtration rate, mL/min/1.73 m |
82.1 (71.8, 94.8) | |
Total cholesterol, mmol/L | 4.29 (3.65, 5.24) | |
Triglycerides | 1.46 (1.11, 2.09) | |
High-density lipoprotein cholesterol, mmol/L | 1.00 (0.88, 1.26) | |
Low-density lipoprotein cholesterol, mmol/L | 2.90 (2.24, 3.55) | |
Glycosylated hemoglobin, % | 6.2 (5.8, 6.9) |
Data are expressed as n (%), mean
*Acute coronary syndrome includes patients with unstable angina and myocardial infarction within 30 days of procedure.
Variable | Total (N = 175) | Non-FP (N = 112) | FP (N = 63) | p-value | |
Location of culprit lesion (%) | 0.433 | ||||
Left anterior descending artery | 55 (31.4) | 33 (29.5) | 22 (34.9) | ||
Left circumflex artery | 42 (24.0) | 25 (22.3) | 17 (27.0) | ||
Right coronary artery | 78 (44.6) | 54 (48.2) | 24 (38.1) | ||
PCI in interrogated vessels (%) | 14 (8.0) | 5 (4.5) | 9 (14.3) | 0.022 | |
Baseline RWS |
11.2 (9.9, 12.5) | 10.8 (9.7, 11.7) | 11.8 (10.7, 13.7) | ||
Baseline RWS |
53 (30.3) | 23 (20.5) | 30 (47.6) | ||
Baseline angiographic and physiological parameters | |||||
Minimal diameter, mm | 2.1 (1.8, 2.4) | 2.2 (1.9, 2.5) | 2.1 (1.8, 2.4) | 0.123 | |
Reference diameter, mm | 3.4 (3.0, 3.6) | 3.4 (3.0, 3.6) | 3.3 (2.8, 3.6) | 0.179 | |
Diameter stenosis, % | 35 (29, 40) | 34 (29, 39) | 35 (30, 40) | 0.474 | |
Lesion length, mm | 16.3 (12.2, 23.2) | 17.3 (12.5, 22.5) | 14.6 (11.7, 22.0) | 0.179 | |
Vessel QFR | 0.94 (0.90, 0.96) | 0.94 (0.90, 0.96) | 0.93 (0.89, 0.95) | 0.065 | |
Lesion-specific |
0.04 (0.02, 0.06) | 0.04 (0.02, 0.06) | 0.04 (0.03, 0.06) | 0.902 | |
Follow-up angiographic and physiological parameters | |||||
Minimal diameter, mm | 2.1 (1.8, 2.4) | 2.2 (2.0, 2.5) | 1.9 (1.6, 2.3) | ||
Reference diameter, mm | 3.2 (3.0, 3.6) | 3.3 (3.0, 3.5) | 3.2 (2.9, 3.6) | 0.463 | |
Diameter stenosis, % | 35 (29, 42) | 32 (27, 39) | 41 (35, 45) | ||
Lesion length, mm | 18.4 (13.1, 23.5) | 17.8 (12.5, 22.8) | 19.1 (13.5, 25.3) | 0.177 | |
Vessel QFR | 0.93 (0.88, 0.95) | 0.94 (0.91, 0.96) | 0.89 (0.84, 0.93) | ||
Lesion-specific |
0.05 (0.03, 0.07) | 0.03 (0.02, 0.05) | 0.06 (0.05, 0.09) |
Data are expressed as n (%) or median (25th, 75th percentiles). FP, functional
progression; PCI, percutaneous coronary intervention; RWS, radial wall strain; RWS
According to the established cut-off value, lesions were divided into high
(RWS
Changes in lesion-specific QFR from index to follow-up
procedures according to baseline RWS
Univariable generalized linear mixed-effects regression analysis showed that
RWS
1-U increase in RWS |
RWS | |||||
OR | 95% CI | p-value | OR | 95% CI | p-value | |
Unadjusted | 1.267 | 1.105–1.453 | 0.001 | 3.617 | 1.823–7.176 | |
Model 1 | 1.270 | 1.106–1.458 | 0.001 | 3.678 | 1.835–7.374 | |
Model 2 | 1.269 | 1.099–1.464 | 0.001 | 3.317 | 1.609–6.838 | 0.001 |
Model 3 | 1.237 | 1.066–1.436 | 0.005 | 2.871 | 1.343–6.138 | 0.007 |
Values are presented as ORs (with 95% CIs) derived via generalized linear
mixed-effects logistic regression analysis. Model 1: adjusted for age, sex,
interval time between CAG measurements. Model 2: Model 1 + adjusted for clinical
risk factors (acute coronary syndrome; diabetes mellitus; eGFR); Model 3: model 2
+ adjusted for angiographic risk factors (PCI in interrogated vessels and
baseline vessel QFR). RWS, radial wall strain; RWS
Receiver operator curves of baseline RWS
In the current study, we used a novel angiography-based approach to quantify the
RWS in intermediate coronary lesions and investigated the impact of focal plaque
strain on the longitudinal changes in coronary physiology. The major findings
were as follows: lesions with a higher RWS
Palpography and elastography using intravascular imaging are the major methods to evaluate coronary strain by detecting differences in the deformability of the vessel wall [4, 16, 17]. However, the clinical application of biomechanical assessment is limited because of the invasive nature of intracoronary imaging and the complexity of the computational methodology. In this regard, Hong et al. [6] proposed a simplified parameter labelled radial wall strain to assess the local mechanical properties of coronary plaques. This novel method can be widely applied in biomechanical assessment because it can be easily obtained from the routine coronary angiograms. In the present study, we analyzed the plaque strain using this angiography-derived RWS at baseline and monitored the dynamic change in hemodynamic status at a median follow-up of 1 year. Our findings showed that lesions with high baseline RWS presented an accelerated functional progression rate, whereas low RWS is associated with plaque stabilization. To the best of our knowledge, this is the first study demonstrated that biomechanical stress plays an important role in the functional progression of medically treated coronary lesions, which may provide clinical evidence linking the high plaque strain and the unfavorable outcomes for CAD patients.
The clinical significance of changes in coronary physiology has been investigated by several wire-based or imaging-derived fractional flow reserve (FFR) parameters [9, 10, 11, 18, 19]. As reported in a previous study, the longitudinal physiological progression is slow, as evaluated by per-vessel FFR with a median decrease of 0.007 per year [9]. A recently published study revealed that the lesion-specific computed tomography-derived FFR value was not significantly different over a mean interval of 13.9 months in patients with intermediate coronary stenosis [10]. In line with these studies, our results showed that vessel-level QFR deteriorated by 0.01 [0, 0.02] over a period of 1 year. In parallel, the overall lesion-specific QFR values also showed a slow progression rate (from 0.04 [0.02, 0.06] at baseline to 0.05 [0.03, 0.07] at follow-up). Despite coronary lesions progressing at a very slow rate in functional status, several studies, including a prospective trial, have demonstrated that intensive statin treatment could improve the hemodynamic status assessed by invasive or computational FFR [10, 11, 19], indicating that serial changes in coronary physiology could be a surrogate marker for monitoring the effect of medical treatments in patients with CAD. In this study, we further demonstrated that angiography-based QFR allowed the assessment of changes in coronary physiology of intermediate lesions and could be a useful quantitative index to evaluate coronary functional progression.
Previous studies have reported that high radial strain is associated with
vulnerable plaque features and a worse prognosis in patients with CAD [5, 20].
However, the underlying mechanism remains unclear. The intracoronary imaging
studies demonstrated that the major causes of acute coronary syndrome are plaque
rupture and erosion, which are prone to occur at the site of high stress within
the cap of a vulnerable plaque [21, 22]. Therefore, the combination of
morphological vulnerability, characterized by thin fibrous caps and large lipid
pools, and biomechanical vulnerability, evaluated by shear stress, plaque
structural stress, or coronary strain, could improve the accuracy in the
detection of high-risk plaque at high risk for adverse coronary event [22, 23, 24]. Of
note, although most of the acute coronary syndromes are provoked by abrupt
rupture or erosion of plaque that leads to subsequent occlusive thrombosis,
recent intracoronary OCT studies have revealed that the majority of ruptured or
eroded plaques remain clinically silent and experience a so-called healing
process, which can be visualized as a plaque with layered phenotype on OCT images
[22, 25, 26]. Furthermore, a recent OCT-based study found the layered plaque was
an independent predictor of subsequent rapid lesion progression assessed by
angiographic severity of the luminal narrowing, indicating silent plaque rupture
and subsequent healing may be an important underlying mechanism in the
development of atherosclerotic plaque [27]. Two recent studies have reported that
high RWS levels are associated with an increased risk of OCT-defined vulnerable
features (i.e., high lipid-to-cap ratio and the presence of thin-cap
fibroatheroma) and short-term clinical outcomes, which provides the direct
evidence supporting the clinical relevance between RWS and poor prognosis.
Notably, the optimal threshold of RWS
Several potential limitations should be taken into account. First, this was a
single center, retrospective observational study with a relatively small
population enrolled due to rigorous inclusion and exclusion criteria, raising
concerns for possible selection bias. Second, angiographic and physiological
parameters as well as coronary strain were evaluated using a computational method
based on coronary angiography, the gold standard techniques, i.e., wire-based
FFR, intravascular imaging and palpography, were not performed because of the
retrospective nature of the study. Nevertheless, angiography-derived RWS and QFR
might be the more promising tools for the comprehensive evaluation of high-risk
plaques in clinical settings because of their cost-efficiency and time-saving
nature. Third, there is currently no consensus regarding on the cutoff value for
the definition of significant coronary functional progression. As the change in
coronary physiology is a continuous variable, we defined the functional
progression as any increase in lesion-specific
For intermediate coronary lesions treated with medication, a high RWS level derived from coronary angiography was an independent predictor of subsequent plaque progression in coronary physiology.
The datasets generated and analyzed during the current study are not publicly available due to the institution policy but are available from the corresponding author on reasonable request.
JC, YL, WY, and XL designed the research study. JC, YL, YY, HL, DY, FP, ZY, and FC performed the research and collected the data. JC, GZ, and TY analyzed the data. JC and YL drafted the manuscript. WY, FC, and XL reviewed and modified the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Tongji Hospital, Tongji University (No. K-W-2020-016). All participants provided written or verbal informed consent.
We would like to thank the team of Professor Shengxian Tu at Shanghai Jiao Tong University and Junyi Liu from Pulse Medical for providing technical support.
This study was supported by the National Natural Science Foundation of China (No.82170346), Grant of Shanghai Science and Technology Committee (No.19XD1403300 and 22Y11909800) and Shanghai Municipal Health Commission (No.2019LJ10). Jiapeng Chu is funded by China Scholarship Council (file number: 202206260277).
The authors declare no conflict of interest.
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