A Preliminary Study of Wall Shear Stress in Carotid Artery Stenting

DOI: https://doi.org/10.21203/rs.3.rs-2898568/v1

Abstract

Objective: To characterize carotid wall shear stress (WSS)following carotid artery stenting (CAS) in patients with carotid stenosis. 

Methods: Twenty-eight patients with carotid stenosis treated with CAS between March 2021 to May 2022 in the eighth medical center of the PLA General Hospital were selected for our study. Carotid ultrasound was performed before the operation, one week post-operation, and six months post-operation. Carotid artery WSS was detected by blood flow vector imaging, and the changes in WSS before and after the operation were collected. Genetic testing of drugs was detected for patients with restenosis. 

Results: Pre-operative WSS of the proximal, narrowest region, and distal carotid arteries in patients with ischemic carotid artery stenosis was 7.88±3.18Pa, 14.36±6.66Pa, and 1.55±1.15Pa, respectively. Comparatively, pre-operative WSS of the proximal, narrowest region and distal carotid arteries in patients without ischemic symptoms was 5.02±1.99Pa, 9.68±4.23Pa, and 1.10±0.68Pa, respectively, with a significant difference between the two groups (p<0.001). Overall WSSof the proximal, narrowest region, and distal carotid arteries in patients before CAS was 6.68±3.0Pa, 12.47±5.98Pa, and 1.39±0. 96Pa. WSS of the proximal, narrowest region, and distal carotid was 4.15±1.42Pa, 6.71±2.64Pa, and1.86±1.13Pa one week after CAS, compared to 4.44±1.91Pa, 7.90±4.38Pa, and 2. 36±1.09Pa six months after CAS. WSS of the proximal and narrowest region of the carotid artery was reduced after carotid stenting, and the difference was statistically significant (p<0.001). There was no statistically significant difference in WSS between one week and six months after stenting (P > 0.05). 

Conclusion: Changes in carotid WSS are closely related to carotid stenosis, which can provide important hemodynamic information for the treatment of CAS. The technique has important application value in pre-operative evaluation, curative effect evaluation, and long-term follow-up.

Introduction

Carotid artery stenosis and ischemic stroke are intimately linked, with about 20% of strokes caused by extracranial carotid artery stenosis [1, 2]. Over time, symptomatic patients with 50–70% stenosis exhibit a history of transient ischemic attack (TIA) or cerebral infarction, and for asymptomatic patients with 70–99% stenosis, stenting has become a mainstay treatment [3]. The most common cause of carotid artery stenosis is arteriosclerosis, and the evolution of arteriosclerotic plaque is closely linked to local hemodynamics factors. Studies have shown that low carotid wall shear stress (WSS) can lead to increased blood retention at the carotid artery, resulting in the enhanced deposition of lipoproteins. At the same time, the production of vascular endothelium damaging factors can increase while that of the protective factors can decrease, thereby promoting the development of arteriosclerosis. Increased WSS can inhibit platelet-derived growth factor (PDGF) secretion, reduce vascular smooth muscle protein synthesis, and inhibit vascular endothelial cell proliferation, ultimately leading to thinning and rupture of the arteriosclerotic plaque fibrous cap [410]. At present, there are few studies characterizing changes in WSS after CAS. As such, the purpose of this study was to analyze changes in WSS in patients with carotid artery stenosis before and after CAS.

Patients and Methods

Patients

A total of 28 patients with carotid artery stenosis were selected from the Department of Neurology of the Eighth Medical Center of PLA General Hospital, Beijing, China, between March 2021 and May 2022.

Inclusion criteria: Internal carotid artery stenosis confirmed to be 50–99% by carotid ultrasound and cranial magnetic resonance angiography (MRA) or cranial computed tomographic angiography (CTA) or angiography due to arteriosclerotic changes. Among them, patients with 50–70% stenosis presented a history of TIA or cerebral infarction. Diagnostic criteria were based on the NASCET carotid endarterectomy trial [11]. Wall shear testing was performed preoperatively, after which patients' informed consent to participate in our study was obtained.

Exclusion criteria: (1) allergy to iodine contrast medium, (2) severe systemic organic diseases of the heart, liver, or lung (3) severe bleeding tendency and thrombocytopenia, (4) complete occlusion of the carotid artery, (5) prior carotid endarterectomy, (6) Non-atherosclerotic carotid artery stenosis, and (7) patients who could not undergo CAS due to other conditions.

Pre-operative Preparation

Patients were given oral clopidogrel (75 mg/d) and aspirin (100 mg/d), as well as atorvastatin calcium tablets (20–40 mg/d) at least seven days before the operation. Patients fasted and were deprived of water six hours before the operation. Blood routine examinations, blood glucose level, liver and kidney function, myocardial enzymes, electrolytes, coagulation status, ECG, and cardiac function evaluation were collected and performed before the operation.

WSS Examination

Using a Resona9 Color Doppler Ultrasound Diagnostic Apparatus (Shenzhen Mindray Biomedical Electronics Co. Ltd., Shenzhen, China), patients were positioned in the supine position with their necks fully exposed. The largest longitudinal section of the middle segment of the common carotid artery was identified. The lumen of the common carotid artery was centered at the middle of the sampling frame in the horizontal Flow imaging mode. While keeping the probe still for 1.5 s, the “Update” button was then pressed to store V-Flow dynamic images. Flow dynamic images were collected at the proximal, narrowest, and most distal longitudinal sections of the carotid artery. The images were stored and analyzed, and the average WSS of the proximal, narrowest, and distal segments of interest were measured. More specifically, each of the proximal, narrowest, and distal sections of the carotid artery was divided artificially into six sections, and the average of six wall stress measurements was calculated to give the mean WSS. Wall shear tests were performed preoperatively, one week post-operatively, and six months post-operatively.

In the V-flow mode, high velocities were represented by red vectors, medium velocities by yellow and orange vectors, and low velocities by green vectors. The length of the vector arrow represents the flow velocity. The WSS value is calculated by the following:

Where τ is WSS, µ is blood viscosity; \(\overrightarrow{w}\) denotes the direction of \(\overrightarrow{{\tau }}\) and is a unit vector;\(\overrightarrow{{\text{v}}_{\text{i}}}\)is the vector velocity; N is the number of velocities used for WSS estimation;\(\varDelta\)ri is the distance from the ith velocity measurement to the WSS measurement location [12].

Carotid Artery Stenting

After local anesthesia, the femoral artery was punctured using Seldinger's technique, and an 8F arterial sheath was inserted. Utilizing a .035 inch misgurnus guide wire, the 8F guide catheter was positioned in the middle segment of the common carotid artery of the affected side, and the umbrella was sent through the stenosis along the guide wire to the distal part of C1 segment and released. After the balloon was removed, the self-expanding stent was inserted into the carotid artery. After the stent was released, the stent delivery system was removed.

Statistical Analysis

Data were processed using SPSS 26.0 software. Continuous data were consistent with the homogeneity of variance of the normal distribution. Continuous data between two groups were compared using independent-sample t-tests, and within-group comparisons at different time points were compared using repeated-measures analysis of variance, presented as mean ± standard deviation. Two-sided t-tests were deemed significant with p < 0.05.

Results

Patients Characteristics

A total of 28 patients were enrolled, including 24 males and 4 females. The average age was 67.11 ± 7.87 years, with a full range from 54 to 79 years old. Among the 28 participants, 2 had experienced transient ischemic attacks from the carotid system, 13 had experienced cerebral infarction, and 13 had asymptomatic carotid stenosis. 19 participants had hypertension, 15 had diabetes, 14 had coronary atherosclerotic heart disease, 8 had hyperlipidemia, and 7 had a history of cerebral infarction. All patients were examined using cervical vascular ultrasound and transcranial Doppler ultrasound, as well as head MRI, MRA, or CTA before the operation. All patients underwent cerebral angiography to confirm carotid artery stenosis, all of which were deemed moderate to severe stenosis. Stenosis was located at the end of the common carotid artery and the initial segment of the internal carotid artery in 23 cases, a simple initial segment of the internal carotid artery in 5 cases, and bilateral internal carotid artery stenosis in 3 cases (Table 1).

Table 1

The baseline data of stenotic carotid artery patients.

 

Value or number

Age (year)

67.11 ± 7.87

Sex

 

Female

4

Male

24

Side of the carotid artery

 

Right

16

Left

12

Clinical symptoms

 

Transient ischemic attack

2

Cerebral infarction

13

Asymptomatic

13

History

 

Hypertension

19

Diabetes

15

Coronary heart disease

14

Hyperlipidemia

8

Cerebral infarction

7

DSA findings

 

Moderate carotid stenosis

9

Severe carotid stenosis

19

Location

 

Internal carotid artery

5

Carotid bifurcation

23

Wall Shear Stress Examination

The degree of carotid stenosis was 50% − 69% in 9 of 28 patients. WSS in the proximal, narrowest, and distal regions of the stenosis was 4.78 ± 2.63Pa, 8.43 ± 4.19 Pa, and 1.39 ± 1.38 Pa, respectively. 19 patients had 70% − 99% carotid stenosis, with proximal, narrowest, and distal WSS of 7.38 ± 2 88 Pa, 13.97 ± 6.05 Pa, and 1.32 ± 0.75 Pa. WSS at the proximal and narrowest regions of the stenosis was significantly increased based on the severity of the stenosis. WSS at the distal end of the stenosis decreased, with no statistically significant difference between the two groups (Table 2). In the 15 patients with cerebral infarction or transient ischemic attack, WSS of the proximal, narrowest, and distal regions of stenosis were 7.88 ± 3.18 Pa, 14. 36 ± 6. 66 Pa, and 1.55 ± 1.15 Pa, respectively. In the 13 patients without ischemic symptoms, the WSS in the proximal, narrowest, and distal parts of stenosis were 5.02 ± 1.99 Pa, 9.68 ± 4.23 Pa, and 1.10 ± 0.68 Pa, respectively. Compared to the patients without ischemic symptoms, the WSS in the proximal and narrowest parts of stenosis in patients with carotid stenosis accompanied by ischemic symptoms was significantly increased. WSS in the distal parts of stenosis was also increased, albeit without statistical significance (Table 3).

Table 2

wall shear stress in patients with different degrees of stenosis

Locations

50–69%

70–99%

t

P

Proximal of stenosis (Pa)

4.78 ± 2.63

7.38 ± 2.88

-2.292

0.030

Narrowest region of the carotid artery (Pa)

8.43 ± 4.19

13.97 ± 6.05

-2.471

0.020

Distal of stenosis (Pa)

1.39 ± 1.38

1.32 ± 0.75

-0.179

0.859

Table 3

wall shear stress in patients with or without ischemic symptoms

Locations

without

with

t

P

Proximal of stenosis (Pa)

5.02 ± 1.99

7.88 ± 3.18

-2.799

0.010

Narrowest region of the carotid artery (Pa)

9.68 ± 4.23

14.36 ± 6.66

-2.178

0.039

Distal of stenosis (Pa)

1.10 ± 0.68

1.55 ± 1.15

-1.251

0.222

Comparison of carotid wall shear stress before and after stenting

Before the operation, the shear wall stress of the proximal, narrowest, and distal portions of stenosis in the 28 patients was 6.68 ± 3.35 Pa, 12.47 ± 5.98 Pa, and 1.39 ± 0. 96 Pa, respectively. Ultrasound examination showed that the degree of stenosis was less than 50% within one week after stenting, and the shear stress of the proximal, narrowest, and distal sections was 4.15 ± 1.42 Pa, 6.71 ± 2.76 Pa, and 1.86 ± 1.13 Pa. Compared with pre-operative results, the WSS of the proximal and narrowest area of stenosis decreased one week after the operation, while the distal WSS increased, all with statistical significance. Six months after stenting, ultrasound showed that the degree of stenosis in 27 patients was less than 50% and more than 50% in 1 patient. Shear wall stress at the proximal, narrowest, and distal portions was 4.44 ± 1.91 Pa, 7.90 ± 4.38 Pa, and 2.44 ± 1.09 Pa, respectively. Compared to preoperatively, WSS at the proximal and narrowest regions of stenosis was decreased, while WSS at the distal region was increased at six months post-operation. All differences were statistically significant. There was no statistically significant difference in shear wall stress of the proximal, narrowest, and distal sections between six months and one week post-operatively (Table 4). Representative pre-operative and post-operative images of carotid WSS are shown in Figs. 1,2,3.

Table 4

Comparison of wall shear stress before and after stenting

Locations

Time

F

P

pre-operative

1 week post-operatively

6 months post-operatively

Proximal of stenosis (Pa)

6.68 ± 3.0

4.15 ± 1.42*

4.44 ± 1.91*#

27.276

< 0.001

Narrowest region of the carotid artery (Pa)

12.47 ± 5.98

6.71 ± 2.64*

7.90 ± 4.38*#

25.725

< 0.001

Distal of stenosis (Pa)

1.39 ± 0.96

1.86 ± 1.13*

2.36 ± 1.09*#

19.995

< 0.001

Note: for pairwise comparisons, * indicates P < 0.05 compared to shear stress pre-operative, # indicates P > 0.05 compared to shear stress 1 week post-operatively.

Discussion

WSS is the frictional force exerted in parallel to the endothelial surface of the vessel wall by blood viscosity. It is considered a major parameter to assess the risk of atherosclerosis. Traditional color Doppler ultrasound imaging only measures the velocity component of blood flow along the direction of ultrasonic propagation, but it cannot image the blood flow perpendicular to the direction of ultrasonic propagation. This technique provides accurate data on the velocity component of blood flow only under the laminar flow condition. Hence, it is almost impossible to obtain the correct blood flow velocity component for calculating WSS in a complex blood flow state. The v-flow technique can provide directional information on blood flow velocity and help obtain accurate blood flow velocity components for WSS toward more accurate evaluation [13].

WSS is also considered an important cause of the development of carotid atherosclerosis. The measurement of WSS in the carotid artery is typically performed via magnetic resonance imaging or enhanced CT, with three-dimensional reconstruction and calculation by software. Comparatively, flow vector imaging can visualize and quantify the flow field and hemodynamics in the lumen of blood vessels, detect eddy currents and countercurrents, and detect WSS. Thus far, it has been widely used in the diagnosis, evaluation, and treatment of cardiovascular diseases [1417]. Vector flow imaging (VFI) is an angle-independent technique that measures and visualizes the blood flow velocities in all directions, thereby providing intuitive and quantitative images of vortex formation. Assessment of disturbed blood flow patterns at the carotid bifurcation has the potential to allow a better understanding of the diagnostic value of complex flow patterns, enhancing the risk stratification efficiency [13, 18]. It can also evaluate hemodynamic changes during moderate to severe carotid stenoses [8]. Moerman et al. performed MRI imaging of the carotid bifurcations of patients scheduled for carotid endarterectomy surgery. This study compared local WSS metrics and histological characteristics of plaque vulnerability in carotid plaques, revealing that necrotic core sizes and macrophage activation areas are significantly larger in areas exposed to high time-averaged WSS or low-oscillatory shear index [19]. More recently, flow vector imaging to assess arteriosclerotic carotid artery stenosis hemodynamics has been increasingly studied[13], but less research has specifically focused on patients undergoing CAS.

Our findings that WSS is increased in the distal and lower in the proximal portions of carotid artery stenosis further suggests that decreased proximal WSS may aggravate intima-media thickening and promote plaque formation, and increased distal wall shear may increase the risk of plaque rupture. Compared with patients with carotid artery stenosis without ischemic symptoms, patients with ischemic symptoms had higher WSS proximal and at the narrowest portion of stenosis, indicating that the higher the WSS in the narrowest area, the greater the risk of plaque rupture and detachment. This is in line with the literature reporting that wall shear obtained by measuring peak systolic velocity at the narrowest portion of stenosis can be a better predictor of ischemic stroke than the degree of stricture [20, 21] .

The results also showed that the patients with 70–99% stenosis had higher WSS in the proximal and narrowest regions compared to patients with 50–69% stenosis, indicating a positive correlation between WSS and severity of stenosis, consistent with the literature [19]. After stenting, WSS decreased in the proximal and narrowest region, with a larger decrease in the narrowest region. There was no significant change in WSS of the proximal, narrowest, or distal regions six months post-operation compared with one week post-operation. In 1 of 28 cases, the shear stress of the proximal and narrowest regions increased significantly. In this single case, the blood flow velocity increased, the vortex ratio increased, and the degree of stenosis was 70%. The restenosis was indicated by angiography. Notably, the case’s gene analysis showed that the genotype for clopidogrel was CYP2C19 * 2/* 17, and the genotype for statins was SLCO1B1 * 1a/* 1b, apoe E3E4. The patient is currently under follow-up after being transitioned from clopidogrel to ticagrelor and having ezetimibe added as a lipid-lowering drug along with atorvastatin calcium.

At present, the application of blood flow vector imaging to measure WSS of the carotid arteries is rare in the clinical setting. Notably, this is a self-contrast study. The number of cases included in this study is small and only from a single center, which limits the generalizability of our results. WSS affects the morphology, intimal proliferation, differentiation, metabolism, and communication of endothelial cells [22]. By controlling the near-wall transport processes involved in atherosclerosis, such as low-density lipoprotein, nitric oxide, adenosine triphosphate, oxygen, monocyte chemoattractant protein-1, etc.[23]. Our study did not examine the relationships between shear stress, endothelial cells, and related biochemical mass transport models. Further studies are needed to understand the long-term value of shear stress testing post-CAS because the technique has yet to be compared to repeat cerebral angiography, particularly in regard to in-stent restenosis.

In conclusion, ultrasonic measurement of WSS provides important hemodynamic information in patients with carotid artery stenosis before stent implantation to help determine severity and treatment options. The therapeutic effect can be evaluated after stenting, providing key long-term follow-up value.

Declarations

Ethics approval and consent to participate

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by  The First Medical Center of PLA General Hospital Ethics Committee. All participants read a participant information sheet and provided informed consent prior to the interview. All methods were carried out in accordance with relevant guidelines and regulations.

Consent for publication

Not applicable.

Availability of data and materials

Original data to support the results of this study are not publicly available due to privacy reasons of patients, but are available from the corresponding author upon reasonable request.

Competing interests

The authors declare that they have no competing interests.
     Funding

Not applicable.
  Authors' contributions (This statement must exactly match on Editorial submission system and in the manuscript)

Tao Xiaoyong and Chen Yuping have made substantial contributions to design and have been involved in drafting of the manuscript. Huang Wei has made substantial contributions to design and revised the manuscript. Qiu Feng and Li Zhuo has made substantial contributions to the design and given final approval of the version to be submitted. Chen Juan has made substantial contributions to statistical analysis and interpretation of data. All authors read and approved the final manuscript.
     Acknowledgements

None.

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