Association between carotid ultrasound features and the detection of functionally significant coronary artery stenosis: a prospective study based on quantitative flow ratio

Introduction

Atherosclerotic cardiovascular disease remains a leading cause of vascular disease worldwide (1). Atherosclerosis is a systemic condition that affects multiple vascular regions, including the coronary arteries (1). Patients with coronary artery disease (CAD) have a higher risk of cardiovascular events and death (2). In patients with CAD, the physiologic significance of coronary stenosis, referring to its impact on myocardial perfusion and ischemia, is an important prognostic indicator (3). Accurate and early diagnosis of functionally significant coronary artery stenosis (CAS) is crucial for effective treatment and improved patient outcomes. As a valuable non-invasive tool in assessing cardiovascular risk, carotid ultrasound has provided insights into the condition of the carotid arteries, which are indicative of systemic atherosclerosis (4,5).

Quantitative flow ratio (QFR) is a novel, image-based computational method used by interventional cardiologists to assess functionally significant CAS. Unlike fractional flow reserve, QFR does not require the use of a pressure wire or hyperemic agents for evaluating CAD (3). This non-invasive method uses angiographic images to calculate blood flow in the coronary arteries, providing insights into the effects of coronary lesions. QFR demonstrates high diagnostic accuracy in evaluating functionally significant CAS, showing a strong correlation and agreement with fractional flow reserve (r=0.863, P<0.001) (6). Thus, QFR has received certification from the U.S. Food and Drug Administration (FDA), establishing it as the “new standard” for the evaluation of functionally significant CAS (7).

Previous research has demonstrated that doppler ultrasound assessments of carotid arteries are highly predictive of clinically significant CAS on angiography (8). Held et al. (9) reported the presence of carotid plaque was a significant predictor of coronary events. Carotid ultrasound shows great potential in predicting coronary vulnerable plaques and stroke risk (10,11). Additionally, plaque evaluations have been found to be superior to intima-media thickness (IMT) measurements in predicting such events. However, despite the established correlation between carotid artery assessments and coronary events, there remains a need for more comprehensive studies that delve into the diagnostic capabilities of carotid ultrasound features in identifying functionally significant CAS. Functionally significant CAS, defined by a QFR value of ≤0.8, represents a critical threshold for clinical intervention and management (7).

This prospective study aimed to evaluate the diagnostic performance of carotid ultrasound features in identifying functionally significant CAS, defined by a QFR value of ≤0.8 (7). By examining the relationship between functionally significant CAS and carotid ultrasound parameters, such as IMT, carotid artery internal artery diameter (IAD), and the presence of carotid plaques, this study sought to enhance the understanding and clinical application of carotid ultrasound in cardiovascular risk stratification. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1528/rc).

Methods

Study population

This prospective study enrolled patients with suspected CAD based on clinical symptoms, risk factors, or abnormal non-invasive tests. A total of 82 patients with stable CAD were selected between September 2022 and November 2023. The exclusion criteria were as follows: age <18 years; abnormal baseline wall motion; previous myocardial infarction; a history of coronary artery bypass surgery; unstable angina; second-or third-degree atrioventricular block; chronic obstructive pulmonary disease; severe valvular heart disease; severe ventricular arrhythmias; severe liver and kidney dysfunction; history of allergy to echocardiography contrast agents; any intracardiac shunt procedures; pregnancy; and breastfeeding.

All patients underwent carotid ultrasound during the same time period before coronary angiography and QFR measurements. Based on the QFR value, the patients was divided into QFR >0.8 and QFR ≤0.8 groups. The baseline characteristics of the participants included hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg), diabetes mellitus [fasting blood glucose (GLU) ≥7.0 mmol/L], smoking history (any record of smoking behavior), and drinking history (frequency and quantity of alcohol consumption). Systolic arterial pressure and heart rate were measured in a resting state, concurrently with carotid ultrasound examinations.

All study participants or their legal representatives provided written informed consent. The study complied with the Declaration of Helsinki (as revised in 2013) and was approved by the Ethics Committees of Fuwai Hospital (No. 2021-1429).

Carotid standard ultrasound

Standard carotid ultrasound examinations were performed for all patients using a commercially accessible ultrasound platform (EPIQ 7C, Philips Healthcare, Andover, MA, USA) at a transducer frequency of 4 to 9 MHz, following the recommendations of the American Society of Echocardiography (5). Briefly, the mean IMT was measured on the far wall of the right and left common carotid arteries (CCA) at sites without plaques. Using two-dimensional ultrasound, the CCA, carotid bifurcation, and internal carotid artery internal artery diameter (ICA-IAD) were measured from near wall inter-adventitial interface to far wall inter-adventitial interface. The blood flow parameters, measured using color Doppler ultrasound, included the internal carotid artery peak systolic velocity (ICA-PSV), end diastolic velocity (ICA-EDV), and resistance index (ICA-RI). Atherosclerotic plaques were defined as focal structures encroaching into the arterial lumen with a height >1.5 mm. High-echo plaque was defined as a type of carotid plaque that appears bright on ultrasound imaging, indicating higher echogenicity. The CCA, carotid bifurcation and ICA were examined on both the left and right sides over the largest possible length proximally and distally. Quantitative measurements of carotid plaque included plaque area, maximum plaque height (MPH), and plaque length (Figure 1). MPH was defined as the maximum distance from the intima-lumen interface to the media-adventitia interface after comparing the vessel walls of both left and right carotid arteries. In each patient, we selected atherosclerotic plaques with the greatest MPH for analyses. All images were analyzed offline using the Qlab 13.0 (Philips Healthcare, Andover, MA, USA). Analysis was performed by technicians blinded to previous imaging and clinical information.

Figure 1 Two-dimensional methods of plaque assessment. Two-dimensional methods of quantifying carotid arterial plaque, including plaque area, MPH and plaque length. IMT is measured in the absence of plaque. MPH, maximum plaque height; IMT, intima-media thickness.

Coronary angiography and online QFR assessment

The images from coronary angiography were interpreted visually by an experienced cardiologist blinded to patients’ echocardiographic data. Two angiographic image runs acquired at different angles ≥25° were transferred by the local network to the QFR system (AngioPlus, Pulse Medical Imaging Technology, Shanghai Co., Ltd., Shanghai, China) that used the same algorithms for QFR computation as previously described. The QFR value was calculated after three-dimensional reconstruction of coronary arteries using the QFR system (12). For each patient, QFR values were calculated separately for the left anterior descending (LAD), left circumflex (LCX), and right coronary artery (RCA). The lowest QFR value among the three coronary arteries (LAD, LCX, and RCA) was selected as the patient’s final QFR value. Critical restenosis lesions were assessed functionally by two trained medical technicians using the QFR measurement software blindly, with their assessments averaged for accuracy. Functionally significant CAS was defined by QFR ≤0.80.

Statistical analyses

According to the normal distribution, continuous variables were reported as mean ± standard deviation (SD) or median with interquartile ranges. Categorical variables were reported as frequencies and percentages. The Shapiro-Wilk test was used to assess the normal distribution. We compared continuous data with either the Mann-Whitney U test or the Student’s t-test, and analyzed categorical data using the Chi-squared or Fisher’s exact tests. Univariate logistic regression identified factors associated with functionally significant CAS. After removing variables with collinearity (either Pearson’s or Spearman’s correlation ≤0.60 or variance inflation factor >10), all relevant carotid ultrasound features and clinical variables were included in the multivariate analysis. Receiver operating characteristic (ROC) curves were generated using QFR as the gold standard to compare the area under the curve (AUC), sensitivity, specificity, 95% confidence intervals, and cutoff values for various parameters. Statistical analyses were conducted with SPSS version 25.0 (IBM, Armonk, NY, USA), MedCalc, version. All tests were two-sided, with P values less than 0.05 indicating statistical significance.

Results

Patient characteristics

This research ultimately included 82 participants, with 63 males and 19 females. All participants underwent carotid ultrasound and QFR assessments. The clinical characteristics of the participants are summarized in Table 1. There were 40 patients (48.8%) with a QFR >0.8, while 42 patients (51.2%) had functionally significant CAS with QFR ≤0.8. No statistically significant differences were found in terms of cardiovascular risk factors between the two groups, except for the significant differences found in GLU, high-sensitivity cardiac troponin I (hscTnI), N-terminal pro-brain natriuretic peptide (NTproBNP), and systolic arterial pressure between the two groups (all P<0.05).

Carotid artery properties

Carotid artery properties are shown in Table 2. Patients with functionally significant CAS (QFR ≤0.8) had greater IMT, bifurcation IAD and ICA-IAD, compared to patients with non-functionally significant CAS, with P values of <0.001, 0.015, and 0.011, respectively. There were no significant differences in blood flow parameters between patients with and without functionally significant CAS.

Table 2 demonstrated that patients with functionally significant CAS have a higher prevalence of carotid plaque and bilaterality of plaques, as well as significantly greater plaque number, MPH, length, and area compared to patients with non-functionally significant CAD (P<0.001). There was no significant difference in the ratio and number of high-echo plaques between the two groups.

Univariate and multivariate analyses for participants with functional significant CAS

In total, 42 patients were diagnosed with functionally significant CAS according to QFR value, as shown in the univariate logistic regression analysis (Table 3). None of the biochemical test results were significant, but participants diagnosed with functionally significant CAS had significant correlations with systolic arterial pressure, IMT, bifurcation IAD, ICA-IAD, MPH, plaque length and area. In the multivariate logistic regression analysis, MPH (odds ratio =1.777, P=0.018) was associated with functionally significant CAS after adjusting for the potential confounders and excluding parameters with collinearity (Table 3).

The value of carotid ultrasound in identifying functional significant CAS

According to the ROC analysis, plaque area had the largest AUC (AUC =0.812) to detect functionally significant CAS among IMT, plaque length and MPH (Figure 2). According to the results of the ROC analysis (Figure 1), the cutoff value of plaque area, IMT, MPH and plaque length were 9.07, 0.945, 2.45 and 5.00, respectively, and the sensitivity and specificity for detection of functionally significant CAS were 85.7% and 70.0%, 61.9% and 77.5%, 61.9% and 72.5%, 85.7% and 62.5%, respectively (Table 4).

Figure 2 ROC curve describing the diagnostic performance of carotid ultrasound to identify functionally significant CAS. IMT, intima-media thickness; MPH, maximum plaque height; ROC, receiver operating characteristic; CAS, coronary artery stenosis.

Discussion

In this study, QFR, an angiographic method estimating coronary blood flow velocity reserve, is the first to be compared with carotid artery features. This study demonstrated that carotid artery features detected by carotid ultrasound are significant, including increased IMT, bifurcation IAD, and ICA-IAD. We also found that carotid plaque parameters (MPH, length, and area) were independently associated with functionally significant CAS, with plaque area demonstrating greater AUC and sensitivity than the others according to the ROC curve. Overall, our study demonstrated that carotid ultrasound is a clinically useful tool for CAD patients with functionally significant CAS.

Coronary atherosclerosis is the primary cause of functionally significant CAS (13,14). Due to atherosclerosis being a systemic condition, there is a mutually reinforcing relationship between carotid and coronary artery atherosclerosis (15,16). Similar to previous research findings, our study found that carotid IMT and plaques were also increased in CAD patients with functionally significant CAS than in non-functionally significant CAS. A previous study of patients with stable angina pectoris demonstrated that carotid IMT and plaques were related to increased risk of cardiovascular death or myocardial infarction (9). Notably, plaques are still more strongly related to events than IMT (17).

This research indicates that arteries can expand to counteract atherosclerosis, maintaining lumen diameter and essential blood flow (18,19). Additionally, arterial enlargement during the progression of subclinical atherosclerosis may affect clinical outcomes (20,21). This compensatory mechanism, however, can vary across different arterial segments. Our research results also confirmed this finding. Notably, in patients with functionally significant CAS, changes in the IAD at the CCA may not be as pronounced as in the bifurcation and ICA. This may be related to differences at the CCA compared to the ICA and bifurcation in terms of anatomical and functional differences, heterogeneity of atherosclerosis, and vascular adaptation mechanisms (22-24). Overall, these differences highlight the importance of segment-specific considerations in cardiovascular research and clinical practice.

Previous studies have demonstrated the significant value of carotid plaque in the clinical diagnosis, treatment, and prognosis of CAD (25-29). The ROC curve analysis in our study revealed that plaque area is a superior marker compared to IMT, MPH, and plaque length for identifying functionally significant CAS, with a cutoff value of 9.07 mm², providing a sensitivity of 85.7% and specificity of 70.0%. Examples showing carotid plaque in patients with QFR ≤0.8 and QFR >0.8 are presented in Figure 3. Plaque area has been increasingly recognized as a more precise and reliable indicator of atherosclerotic burden than IMT and MPH (26,27). Plaque area is a better diagnostic marker because it measures both the volume and distribution of atherosclerosis, unlike IMT and MPH, which only measures wall thickness or height of the plaque. This research supports our current findings that plaque area is a better marker for identifying significant CAS, emphasizing the importance of comprehensive plaque assessment in clinical practice.

Figure 3 The carotid plaque in CAD patients with QFR. The carotid plaque shown in the long-axis view of the common carotid artery. (A-C) Examples of CAD with QFR ≤0.8. (D) An example of CAD with QFR >0.8. CAD, coronary artery disease; QFR, quantitative flow ratio.

Coronary stenoses that cause inducible ischemia are known as functionally or hemodynamically significant stenoses. Identifying these lesions accurately through hemodynamic assessment helps ensure more effective treatment and better survival rates (30). The DEFER study showed that non-significant stenoses, when treated medically, had excellent outcomes over 5 years, with mortality and heart attack rates below 1% per year, and stenting did not improve these results (31). This indicates that revascularization should focus on functionally significant lesions when possible, while stenting non-ischemic lesions are not beneficial. Our study found that carotid ultrasound correlates with QFR, which measures functionally significant coronary lesions. Thus, carotid ultrasound can be a valuable tool for guiding percutaneous coronary intervention in CAD.

Limitations

Despite these promising results, there are several limitations to this study. Firstly, the sample size is relatively small, which may limit the generalizability of the findings. Larger, multicenter studies are needed to validate these results and establish standardized thresholds for carotid ultrasound parameters in diagnosing functionally significant CAS. Secondly, this study’s selection bias may affect the results, as the participants were drawn from a high-risk patient group requiring coronary angiography. Thirdly, the primary limitation of this study is the reliance on two-dimensional (2D) ultrasound imaging for the assessment of carotid plaques. Focusing on only the largest MPH plaque may limit our findings, as other plaque features could provide valuable insights into cardiovascular risk. Future research should consider utilizing three-dimensional (3D) ultrasound imaging and contrast-enhanced ultrasound (CEUS) to provide a more comprehensive evaluation of plaque features (32,33). The cross-sectional design of this study precludes the assessment of causal relationships between carotid ultrasound features and functionally significant CAS. Longitudinal studies are required to determine whether changes in carotid ultrasound parameters over time correlate with changes in CAD severity.

Conclusions

Carotid artery features detected by carotid ultrasound were correlated with the functionally significant CAS. Patients with QFR ≤0.8 had higher IMT, IAD and prevalence of carotid plaque. When adjusted for cardiovascular risk factors, carotid plaque character (MPH) continued to have independent associations with functionally significant CAS. In addition, the negative predictive value and specificity were higher for plaque area ≥9.07 mm² and MPH ≥2.45 mm. We conclude that carotid ultrasound is a useful tool in the non-invasive assessment of functionally significant CAS.

Acknowledgments

We would like to thank Editage (www.editage.cn) for English language editing.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1528/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1528/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Institutional Review Board of Fuwai Hospital (No. 2021-1429), and all study participants or their legal representatives provided written informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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