Imaging modality-dependent carotid stenosis severity variations against intravascular ultrasound as a reference: Carotid Artery intravasculaR Ultrasound Study (CARUS)

doi:10.21203/rs.3.rs-2103615/v1

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Research Article

Imaging modality-dependent carotid stenosis severity variations against intravascular ultrasound as a reference: Carotid Artery intravasculaR Ultrasound Study (CARUS)

https://doi.org/10.21203/rs.3.rs-2103615/v1

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Journal Publication

published 21 Aug, 2023

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Purpose

Different non-invasive and invasive imaging modalities are used to determine carotid artery stenosis severity as a principal parameter in clinical decision-making. We compared stenosis degree obtained with different modalities against intravascular ultrasound (IVUS).

Methods

300 consecutive patients (age 47–83 years, 192 men, 68% symptomatic) with carotid artery stenosis of “≥50%” referred for potential revascularization received as per study protocol (i) duplex ultrasound (DUS), (ii) computed tomography angiography (CTA), (iii) invasive quantitative angiography (iQA) and (iv) the vascular imaging gold standard, IVUS. Correlation of measurements with IVUS (r), proportion of those concordant (within 10%) and proportion of under/overestimated were calculated along with recipient-operating-characteristics (ROC).

Results

For IVUS area stenosis (AS) and IVUS minimal lumen area (MLA), there was only a moderate correlation with DUS velocities (peak-systolic, PSV; end-diastolic, EDV; r values of 0.42–0.51, p < 0.001 for all). CTA systematically underestimated both reference area and MLA (80.4% and 92.3% cases) but CTA error was lesser for AS (proportion concordant-57.4%; CTA under/overestimation 12.5%/30.1%). iQA diameter stenosis (DS) was found concordant with IVUS in 41.1% measurements (iQA under/overestimation 7.9%/51.0%). By univariate model, PSV (ROC area-under-the-curve, AUC, 0.77, cutoff 2.6m/s), EDV (AUC 0.72, cutoff 0.71m/s) and CTA-DS (AUC 0.83, cutoff 59.6%) were predictors of ≥ 50% DS by IVUS (p < 0.001 for all). Best predictor, however, of ≥ 50% DS by IVUS was iQA densitometry (AUC 0.87, cutoff 68%, p < 0.001). On multivariate model, however, CTA came as the sole independent non-invasive diagnostic modality (p = 0.008).

Conclusion

IVUS validation shows significant imaging modality-dependent variations in carotid stenosis severity determination.

carotid stenosis severity

duplex ultrasound

computed tomography angiography

catheter angiography

intra-arterial angiography

intravascular ultrasound

Despite growing understanding of the role of plaque morphology [1–8], stenosis severity remains the fundamental factor in clinical decision-making with regard to recommending medical or interventional therapy to symptomatic and asymptomatic patients with internal carotid artery (CA) atherosclerosis [2,3,9–11].

In the past, major trials used mostly intraarterial quantitative angiography (iQA) for grading ICA stenosis [12,13]. However, iQA poses a non-negligible risk of cerebral ischemic complications (≈ 0.3-3.0%) [14–17]. In addition, iQA needs to be obtained in multiple projections to determine the maximal diameter stenosis [18,19]. Considering safety and economic reasons, iQA has been largely replaced by non-invasive methods including Doppler ultrasound (DUS), computed tomography angiography (CTA) and magnetic resonance angiography (MRA) [20]. These modalities have been employed in more recent trials; often different ones in different trials [12,13,21–24]. Even more importantly, they are also routinely used these days for clinical decision-making including decisions on revascularization [2,3,9–11].

While it has been clear for some time now that discrepancies may exist between the different techniques of carotid stenosis severity evaluation [20,25–27], no systematic validation of the different techniques has been performed against the vascular imaging gold standard – intravascular ultrasound [26–28].

Design

This was a prospective study enrolling consecutive neurologically asymptomatic or symptomatic patients with CA referral stenosis of at least “50%” in the context of potential revascularization. Patients with highly calcified lesions (precluding reliable assessment of velocities as per agreement of 2 experienced ultrasonographers) and those with chronic kidney disease with glomerular filtration rate < 30 ml/minute were excluded.

309 consecutive patients meeting clinical and non-invasive imaging inclusion/exclusion criteria were enrolled to obtain 300 data-sets suitable for analysis. In the case of bilateral disease, the more severe lesion was evaluated unless this was considered too tight for a safe passage with the IVUS transducer. DUS, CTA, and subsequently iQA and IVUS were performed (all examinations within 1 month). In 8 subjects, iQA revealed a ‘string sign’ precluding IVUS visualization of the native carotid lesion. In those cases, IVUS visualization would have required, by agreement of 2 experienced operators, lesion predilatation with a small-diameter balloon (thus losing any relationship between the basal non-invasive measurements). In 1 other patient, there was a failure to save IVUS data. Thus 9 initially considered patients (2.9%) were screening failures in the context of obtaining required data-sets.

Medical treatment prior to iQA and IVUS involved aspirin and a statin. The majority of patients (262/300, 87.3%) were also on an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker.

The study was accepted by the institutional Ethics Committee and all participants provided written informed consent to participate.

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

The authors have no relevant financial or non-financial interests to disclose.

DUS examination

DUS scanning was performed with a Toshiba Aplio PowerVision ultrasound machine (Toshiba Medical Systems Co., Ltd., Tokyo, Japan) equipped with a 4–11 MHz linear-array transducer in a certified vascular ultrasound imaging lab by one of two experienced operators working together on a daily basis. In case of doubt, the other DUS operator was consulted and an agreement was reached. The Doppler waveform was obtained with an angle of insonation equal to 60°, angles between 45° and 60° were considered acceptable in case of anatomic constraints [29,30]. The CA was sampled through the region of stenosis completely until the distal end of the plaque is visualized, to ensure that the site of highest velocity has been located. The highest flow velocities – end diastolic velocity (EDV) and peak systolic velocity (PSV) were recorded. In the first 100 study arteries considered by agreement of the 2 DUS operators appropriate for optimal measurement of diameter stenosis according to the NASCET method, DUS minimal lumen diameter (MLD) and DUS distal reference diameter (RD) were determined by agreement of the ultrasonographers.

Cta

Image acquisition of the supra-aortic vessels was obtained with a 64-multi-detector-row CT system (Somatom 64, Siemens, Erlangen, Germany) using a routine imaging protocol. CTA measurements (including reference area, RA; minimal lumen area, MLA and area stenosis AS) were performed by agreement of 2 senior radiologists with > 20 years and > 15 years of experience in reporting carotid CTA.

iQA

After obtaining transfemoral or transradial access, unfractionated heparin (UFH) was routinely administered at the dose of 5000 IU. In case of cerebral protection device use or post-imaging proceeding to intervention, UFH dose was further titrated to achieve an activated clotting time of at least 250sec. Selective digital angiography of the index carotid artery was performed using Coroscop or Axiom Artis Zee angiograph (Siemens) in multiple (median 4) angulated projections to define the narrowest lumen diameter while minimizing foreshortening and avoiding an overlap of side branches. The view where the stenosis was tightest [18,19] was used for quantitative measurements (Quantcor QA v5.0, Siemens). Measurements (including, RD, MLD, DS, RA, MLA, AS) were performed offline by agreement of two Angiographic Core Lab analysts and were then verified by an angiographic corelab supervisor.

Ivus

Details regarding IVUS images acquisition and analysis are provided in Ref. 31. Consistent with our prior experience [24], the decision to use a neuroprotection device for IVUS imaging was based on the lesion morphology, severity and the presence/absence of a history of ipsilateral clinical symptoms or asymptomatic cerebral infarct, and it was left to the operator performing the case.

In brief, a commercially-available rapid-exchange IVUS catheter (3.5F, scanner diameter 1.15mm Eagle Eye Gold or Platinium, Volcano-Philips Corp.) was introduced to the index ICA over a 0.014-inch coronary guidewire (in case of unprotected imaging or imaging under proximal cerebral protection) or, in case of distal embolic protection device use, over the wire of the protective filter. At least two IVUS runs with automatic motorized pullback were performed with the speed of 0.5mm/sec. ChromaFlo application (Volcano-Philips) was routinely used in one IVUS run to improve the determination of the interface between the lumen and the vessel wall or atherosclerotic plaque [31–33]. In addition, in short, or ambiguous lesions, a very slow manual pullback was additionally performed in order not to miss the minimal lumen site [25]. IVUS measurements of the minimal lumen area (MLA) and distal reference area (RA) were performed at maximal vessel diastole using QIvus software (v.2.0, Medis Medical Imaging Systems). IVUS measurements were performed by agreement of two IVUS corelab analysts with > 10 years of experience in carotid IVUS analysis and were further approved by the IVUS corelab supervisor. The analysts performing DUS, CTA, iQA and IVUS measurements were blinded against one another.

The % diameter stenosis (DS) was computed as [(RD-DS)/RD]*100% according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method [12]. The % area stenosis (AS) was computed as MLA/RA*100%.

Data display and statistical analysis

Categorical variables were presented as numbers and percentages. Continuous variables were expressed, unless specified otherwise, as median and quartiles (Q1-Q3). Receiver operating characteristic (ROC) curves were constructed to assess the accuracy of DUS, CTA and iQA measurements in comparison to IVUS. The overall accuracy was expressed by the area under the ROC curve (AUC; ranging from 0.5 [no relationship] to 1.0 [perfect relationship]). The correlation between DUS/CTA and IVUS was presented as a correlation coefficient (‘r’; ranging from 0 [no correlation] to 1.0 [perfect correlation]). Furthermore, the agreement between quantitative measurements was displayed using histograms and Bland-Altman plots [34]. In addition, the proportion of measurements concordant with IVUS along with those under/overestimated was calculated and displayed in a bar graph format. Concordance with IVUS measurement was defined as a value within ± 10% of the IVUS measurement; values falling below were considered underestimated whereas those falling above were considered overestimated against IVUS as a reference. Mann-Whitney U test was used to assess differences in the distributions between the two groups. A univariate and multivariable model was used to evaluate the predictive value of DUS and CTA for ≥ 50% and ≥ 75% AS by IVUS. The thresholds of 75% AS and 50% DS were used because (with area calculated as π (D/2)) 75% area stenosis corresponds to 50% diameter stenosis [35,36].

A complete imaging package, including DUS PSV and EDV, CTA, iQA and IVUS was obtained in 300 patients; whose clinical characteristics are given in Table 1.

Table 1

Clinical characteristics of the CARUS study patients
n	300
Age, years, median [Q1-Q3]	66 [60.0–72.0]
Womenn (%)	108 (36.0)
Arterial hypertensionn (%)	266 (88.7)
Diabetesn (%)	96 (32.0)
on insulinn (%)	31 (10.3)
CAD	201 (67.0)
h/o myocardial infarctionn (%)	76 (25.3)
smoking (current or past)n (%)	160 (53.3)
PADn (%)	45 (15.0)
BMI, median [Q1-Q3]	27.7 [25.7–30.1]
Creatinine, µmol/L, median [Q1-Q3]	85 [74–101]
30 ≤ eGFR < 60, mL/minn (%)	65 (22.2)

CAD = coronary artery disease, PAD = peripheral artery disease, BMI = body mass index, eGFR = estimated glomerular filtration rate

Table 2 shows baseline characteristics of the study lesions.

Table 2

Baseline characteristics of study lesions
n	300
RICA, n, % LICA, n, %	137 (45.7) 163 (54.3)
PSV, m/s, median [Q1-Q3]	2.5 [1.9–3.3]
EDV, m/s, median [Q1-Q3]	0.9 [0.6–1.2]
Diameter stenosis, % (NASCET), median [Q1-Q3]	69.9 [60.5–77.1]
CTA Area Stenosis (%), median [Q1-Q3]	73 [63–81]

PSV = Peak Systolic Velocity, EDV = End-Diastolic Velocity, NASCET = North American Symptomatic Carotid Endarterectomy Trial method¹²

iQA imaging (that routinely involved anticoagulation with ≥ 5000 IU UFH) and IVUS imaging (with elective use of a proximal or distal cerebral protection device) were uncomplicated. 112 (37.3%) study lesions were evaluated with IVUS in absence of a cerebral protection device use. IVUS imaging was filter-protected in 142 (47.3%) cases, whereas proximal protection was used in 46 (15.3%) cases.

There was a curvilinear relationship between DUS velocities (PSV, EDV) and IVUS-MLA (correlation coefficient of 0.49 and 0.42, respectively) and, similarly, between DUS velocities and IVUS-AS (correlation coefficient of 0.51 and 0.45, respectively, p < 0.001 for all; Fig. 1).

Study data-derived mathematical formulas relating PSV and EDV with MLA and AS by IVUS according to the best-fit curves are provided in Fig. 1.

Figure 2–4 and Suppl Fig. 1–4 demonstrate the relationship between the routine imaging modalities and IVUS measurements in the following order: Panel A - correlation coefficient plot, Panel B - bar chart showing absolute and relative difference against IVUS measurements, Panel C - Bland-Altman plot showing agreement between the methods and any systematic shift, Panel D - bar chart showing the proportion of measurements concordant with IVUS (within ± 10% of the IVUS measurement value) and those over- and underestimated.

DUS MLD and RD measurements were performed in the first 100 (out of 126; 79.4%) study arteries with visualization considered sufficient to appropriately determine stenosis severity according to NASCET. There was only a moderate (though statistically significant) correlation between DUS-MLD and IVUS-MLD (r= 0.35, p<0.001), DUS-RD and IVUS-RD (r= 0.33, p<0.001), and DUS-DS and IVUS-DS (r= 0.41, p<0.001). DUS systematically underestimated MLD and overestimated DS (Suppl Fig 1-I, 1-II, and 1-III, Suppl Table 1).

There was a good correlation between AS by CTA and IVUS (r=0.69, p<0.001, Fig 2). CTA measurements of AS were concordant with IVUS in 57.4% (CTA underestimation in 12.5% cases, overestimation in 30.1%; Fig 2, Suppl Table 1). This occurred despite the CTA systematic underestimation of MLA (92.3% cases) and RA (80.4%) in relation to IVUS (Suppl Fig 2-I and 2-II, Suppl Table 1).

iQA measurements of DS showed concordance with IVUS-DS only in 41.1%. iQA underestimated the IVUS measurement in 7.9%, whereas overestimation in relation to IVUS occurred in 51.0% of cases (Fig 3). Overall, the correlation between DS by iQA and IVUS was acceptable (r=0.63, p<0.001). Data for MLD and RD by iQA vs IVUS are given in Suppl Fig 3-I and Suppl Fig 3-II respectively.

The largest proportion of measurements concordant with IVUS (65.3%, Fig 4) occurred for densitometric evaluation of AS by iQA.

With this technique, comparing automatically the density of the contrast column in the reference segment and at the point, it reaches a minimum, there was a similar proportion of under- and overestimated measurements (14.8% and 19.9% respectively, Fig 4). The relationship between densitometric iQA and IVUS for MLA and RA measurements is presented in Suppl Fig 4-I and Suppl Fig 4-II. The densitometric iQA measurements highly correlated with IVUS (r=0.75 for AS, r=0.82 for MLA, r=0.60 for RA, p<0.001 for all).

ROC analysis identified iQA densitometric measurement of the stenosis severity as the best predictor of IVUS-determined AS ≥75% (AUC 0.88, cutoff 74%, Fig 5). Individual ROC analyses of the predictive values of DUS flow velocities and CTA for IVUS-DS ≥50% and IVUS-AS ≥75% are provided in Suppl Fig 5-I and Suppl Fig 5-II.

Table 3

IVUS validation of DUS flow velocities (PSV, EDV) and CTA area stenosis ≥ 75% against IVUS area stenosis ≥ 75%
AS_IVUS ≥75%
	Cutoff	AUC	sensitivity	specificity	PPV	NPV	p-value
PSV	2.58 m/s	0.77	0.74	0.71	0.64	0.80	< 0.001
EDV	0.75 m/s	0.74	0.77	0.61	0.57	0.80	< 0.001
CTA	72.4%	0.79	0.74	0.71	0.61	0.85	< 0.001
PSV&EDV	n/a	0.77	0.74	0.71	0.64	0.80	< 0.001 for PSV 0.98 for EDV
PSV&EDV &CTA	n/a	0.85	0.79	0.82	0.74	0.85	0.32 for PSV 0.34 for EDV < 0.001 for CT

On univariate model, PSV (ROC area under the curve, AUC 0.77, cutoff 2.6m/s), EDV (AUC 0.72, cutoff 0.71m/s) and CTA DS (AUC 0.83, cutoff 59.6%) were predictors of ≥ 50% DS by IVUS (p < 0.001 for all). Detailed data including sensitivity, specificity and the positive and negative predictive value of PSV, EDV and CTA in determining AS ≥ 75% and DS ≥ 50% by IVUS are given in Table 3 and Table 4.

Table 4

IVUS validation of DUS flow velocities (PSV, EDV) and CTA diameter stenosis ≥ 50% against IVUS diameter stenosis ≥ 50%
DS_IVUS ≥50%
	Cutoff	AUC	sensitivity	specificity	PPV	NPV	p-value
PSV	2.6 m/s	0.77	0.62	0.83	0.87	0.52	< 0.001
EDV	0.71 m/s	0.72	0.68	0.66	0.80	0.51	< 0.001
CTA	59.6%	0.83	0.83	0.68	0.83	0.68	< 0.001
PSV&EDV	n/a	0.77	0.67	0.77	0.85	0.63	< 0.001 for PSV 0.67 for EDV
PSV&EDV &CTA	n/a	0.85	0.75	0.81	0.88	0.63	0.23 for PSV 0.46 for EDV < 0.001 for CT

The multivariable model eliminated PSV and EDV, leaving CTA as a sole (amongst those evaluated in the study) independent non-invasive diagnostic modality to determine carotid stenosis severity (p = 0.008).

Despite accumulating evidence for the role of carotid plaque morphology in relation to the risk of carotid-related cerebral injury and stroke [1–8], current guidelines continue to recommend using stenosis severity thresholds (usually 50% and 70% in symptomatic patients and 60% and 80% in asymptomatic subjects) as the principal parameter in clinical decision-making that includes revascularization by surgical or endovascular route [2,3,9–11].

This is the first prospective study comparing typically used non-invasive modalities (DUS and CTA) against the vascular imaging “gold standard” tool, IVUS, in evaluating the degree of carotid artery stenosis. DUS velocities (PSV, EDV) showed a highly significant though only moderate correlation (coefficient value of ≈ 0.4–0.5) with IVUS measurements of minimal lumen diameter and area stenosis. The relationship was yet weaker between the DUS NASCET and IVUS measurement of MLD and DS, confirming that DUS should not be used as a sole imaging modality to determine management in individuals with carotid stenosis [37–39]. Even with accurate lumen-artery border detection, the one-dimensional ultrasound imaging may lead to underestimation of MLD in case of irregular (eg., elliptic on cross-section) lesion. In our examination, only RD measurement reached better (moderate) accuracy – most likely due to regular, circular shape and better distance/spatial resolution ratio that are naturally more problematic for the minimal lumen.

Our work shows that the sensitivity and specificity of PSV appear acceptable to detect IVUS-confirmed area stenosis of ≥ 75% with the PSV cutoff value of ≈ 2.6m/s (Suppl Fig. 5), and similar findings were obtained for ≥ 50% DS. However, for several reasons, DUS may fail in any precise determination of AS (and DS), particularly in less severe lesions [20,40,41]. First, for anatomic reasons DUS may not show the site of MLD in non-concentric lesions in particular. Another important factor that may reduce the overall accuracy of DUS with respect to the flow velocities may be the presence of contralateral carotid occlusion, leading to the unilateral DUS velocities rise associated with compensatory blood flow increase [42,43]. It has been suggested that the accuracy of non-invasive imaging for the evaluation of cervical carotid artery stenosis may be generally overestimated in the literature [44–46]. This is relevant to clinical practice as – following the methodology of some large trials [refs] – up to 40% CEAs may still be performed today based on isolated DUS measurements [47]. Series comparing non-invasive methods with iQA indicate that the grading of carotid stenosis as medical or potentially surgical remains uncertain in a relatively high proportion of patients, suggesting the use of two imaging modalities for decision-making on revascularization [2]. With DUS use for stenosis degree evaluation, 1 out of 6 arteries would be reclassified by CTA [48]. It should be emphasized that DUS alone is not sufficient to distinguish a non-significant vs borderline (such as 50–60%) carotid stenosis with adequate accuracy [49,50]. This observation is of crucial importance as border-line stenosis (50% for symptomatic and 60% for asymptomatic patients) is a threshold for intervention according to current guidelines [2,3,9–11]. Recent meta-analysis including 809 carotids confirmed a very poor sensitivity (31%) while it indicated a sufficient specificity (84%) for grading 50–69% stenosis with DUS as compared to iQA. DUS accuracy for grading 70–99% carotid stenosis seems to have a higher sensitivity (83%) but much lower specificity (54%) [44]. However, higher rates of DUS-related misclassifications have been reported, particularly in large-diameter arteries [51]. A recent study showed that the qualification to surgical treatment of carotid artery stenosis suffers from a wide variability in carotid velocity thresholds in different DUS laboratories [52]. This directly influences the treatment decision-making [52].

Even though PSV and EDV were univariate predictors of ≥ 75% IVUS-AS (and ≥ 50% IVUS-DS) in the present study (Fig. 5, Suppl Fig. 5), they were both eliminated by CTA in multivariate analysis (Table 3, Table 4). Although this might suggest using CTA as a single diagnostic tool, DUS remains the primary screening modality due to a non-negligible risk of CTA contrast-related complications and cost [2,3,9–11]. We found that although CTA systematically underestimates both MLA and RA, it is highly accurate in AS evaluation (Fig. 2, Fig. 5, Suppl Fig. 5). CTA does not differentiate between the systolic and diastolic flow whereas IVUS takes (in particular – reference) measurements when the vessel reaches its greatest diameter that may be particularly relevant for the reference segment measurements [53]. Moreover, CT diagnostic accuracy is markedly reduced with lesion calcification [54]. Despite these limitations, not only CTA accuracy in detecting ≥ 50% DS and ≥ 75% AS is greater than that of DUS, but also – according to the present analysis – the overall diagnostic accuracy is not increased significantly by adding DUS in the ROC analysis (Table 3, Table 4).

An optimal carotid stenosis screening tool should be both highly sensitive and highly specific (Fig. 5, Suppl Fig. 5). When considering DUS as a screening tool, the velocity threshold should optimally be decreased to the value joining high sensitivity with reasonable loss in specificity to reduce the proportion volume of false-negative results and reduce, at the same time, the number of other examinations (such as CTA) needed for a cross-verification. With the use of only one diagnostic non-invasive method (DUS in particular), a significant proportion of patients may be misclassified into a discordant category (surgical vs. medical), providing an argument for performing both types of non-invasive imaging [48]. In case of discordance between the non-invasive methods, intra-arterial angiography may be needed to determine lesion severity [18,19,32,33]. Once iQA is performed, IVUS may accurately visualize the MLA and RA, assess plaque morphology [31], and provide procedural quality control [56–58].

Important novel information from this study is the high diagnostic accuracy of iQA densitometric measurement (density of a contrast column in MLD in a relation to a RD) that was found to be greater than that of the conventionally-used iQA diameter stenosis.

The magnitude of imaging modality-dependent variations in the numeric “value” of stenosis severity identified in the present study suggests that evidence-based decision-making should consult individual clinical trials and studies with respect to the specific modality used to determine stenosis severity. In case of discrepancies, at least CTA should be employed.

Limitations

This work was limited to the evaluation DUS and CT as non-invasive methods because MRI angiography has been used far less frequently for carotid stenosis severity evaluation both in our Institution and in referring centres. The role of contralateral carotid occlusion (if present) and the potential role of the lesion length on DUS flow velocities require further evaluation.

Physicians should be aware of the variability in carotid stenosis severity determined using different imaging modalities. When using trial data as the basis for clinical decision-making, stenosis severity method(s) should be considered.

Ethical Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Jagiellonian University Ethics Committee (402/184234) and all patients provided written informed consent to participate.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Authors' contributions

All authors contributed to the study conception and design. Material preparation and data collection were performed by Lukasz Tekieli, Anna Kablak-Ziembicka, Wladyslaw Dabrowski, Karolina Dzierwa, Zbigniew Moczulski, Malgorzata Urbanczyk-Zawadzka, Adam Mazurek, Maciej Krupinski, Tadeusz Przewlocki, Piotr Pieniazek and Piotr Musialek. Statistical analysis was performed by Justyna Stefaniak. The first draft of the manuscript was written by Lukasz Tekieli and Piotr Musialek, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by Jagiellonian University Medical College (ZDS/007819, N41/DBS/000822, N41/DBS/000823) and John Paul II Hospital Research Fund.

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Imaging modality-dependent carotid stenosis severity variations against intravascular ultrasound as a reference: Carotid Artery intravasculaR Ultrasound Study (CARUS)

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