Research progress on the influence of local hemodynamics on carotid atherosclerosis

AN Si-long, ZHAO Jian-nong, LIU Zhao-hui

Hainan Medical University, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, China

Keywords:

ABSTRACT The reasons for the formation of atherosclerosis are diverse and complex, and atherosclerosis as a kind of systemic disease has the characteristics of focal selectivity, which occurs in the carotid bifurcation.The feature enables a large number of studies have found that the severe local hemodynamic characteristics has a great influence to the occurrence of this disease.This paper briefly reviews the related research on the local hemodynamics of carotid bifurcation.The relevant parameters of local hemodynamics were sorted out and summarized, and the effects of wall shear force and its derived parameters on the generation, progression and rupture of carotid atherosclerosis and their clinical applications were reviewed, in order to provide mechanical information for the early warning of carotid plaque rupture.At the same time, this paper describes the transformation of local hemodynamics research in the clinical application of carotid atherosclerosis disease, in order to provide personalized selection and basis for the clinical treatment of this disease.

1.Introduction

Ischemic brain disease is an important medical issue facing China’s medical and health system at present, Carotid atherosclerosis causes carotid artery lumen stenosis, while CAS plaque rupture and detachment leads to distal cerebral artery embolism and thus causes ischemic cerebrovascular events.CAS has therefore become one of the main factors for the occurrence of ischemic cerebrovascular diseases[1].Therefore, it is of great significance for the prevention and treatment of ischemic cerebrovascular diseases to clarify the cause and development of carotid atherosclerotic disease and the main influencing factors of the rupture of carotid atherosclerotic plaque.

Atherosclerotic plaque is a chronic inflammatory lesion caused by excessive lipid deposition in the subintima of the middle and great arteries.There are three main mechanisms of atherosclerotic plaque formation: mechanical, inflammatory and physicochemical factors.And there are many clinical factors closely related to it such as: hypertension, diabetes, hyperlipidemia, smoking and so on[2].This suggests that atherosclerosis is a systemic disease affecting the whole body.However, through a large number of anatomical and clinical cases, it has been found that the lesion location of atherosclerotic plaque in arteries is not random, but mostly occurs at the bend and bifurcation of large and medium arteries and other specific areas where blood flow is relatively complex[3].For example, it has been found that about 90% of carotid atherosclerotic plaques occur at the bifurcation of internal and external carotid arteries from the common carotid artery[4].It has been hypothesized that the selective location of this lesion in atherosclerosis is closely related to the characteristics of local hydrodynamics.Studies have shown that hemodynamic factors play an important role in the occurrence and development of atherosclerotic plaques[5].It has been hypothesized that the selective location of this lesion in atherosclerosis is closely related to the characteristics of local hydrodynamics.Studies have shown that hemodynamic factors play an important role in the occurrence and development of atherosclerotic plaques.

2.Local hemodynamics

2.1 Overview of local hemodynamics

Hemodynamics is primarily concerned with the interaction between blood flow in blood vessels and its influence on the body.Later, the study of local hemodynamics of atherosclerosis began in the 1960 s, which was first proposed by Texon.He believed that there was a low-pressure area at the curvature of blood vessels,causing tension to the intima of the artery, which would lead to the formation of atherosclerosis[6].Subsequent studies have demonstrated that carotid atherosclerotic plaques occur at specific sites that are characterized by abnormal wall shear force (WSS).Fry proposed the high-wall shear force hypothesis in 1968, arguing that the highwall shear force generated by blood flow damages the intima of vascular wall, leading to platelet aggregation and atherosclerosis,and that the wall shear force causing intima damage of vascular wall should reach 40 Pa/cm2.However, the value of arterial WSS measured by researchers under human physiological conditions was all below 10 Pa /cm2, so this hypothesis was not supported by researchers.Subsequently, in 1969, Professor Caro et al.in the United Kingdom found that there were lipid streaks and incipients of plaques in the areas with low shear stress in the inner wall of arteries.Subsequently, in 1969, Professor Caro et al.in the United Kingdom found that there were lipid streaks and incipients of plaques in the areas with low shear stress in the inner wall of arteries[7],In 1978, the hypothesis of low wall shear force was proposed, which suggested that low wall shear force on intimal surface of artery could cause deposition of platelets and lipids.Most of the subsequent studies were consistent with this hypothesis.Subsequently, researchers focused on WSS in the study of local hemodynamics of carotid plaque.In addition, new mechanical factors were found in different stages of disease development during the study, which will be described below.

2.2 Local hemodynamic parameters of carotid atherosclerotic plaques

Local hemodynamics of carotid atherosclerotic plaque involves too many related parameters.Based on relevant literature and research methods of fluid-structure coupling of hemodynamics, these parameters are mainly summarized and divided into two categories:hemodynamics related mechanical parameters and vascular geometry related parameters.The author will elaborate on these two main parameters below.

2.2.1 Local hemodynamics and hemorelated mechanical parameters of carotid atherosclerotic plaques

Currently, it is generally believed that WSS is an important hemoflow-related mechanical parameter, which plays an important role in the occurrence and development of atherosclerotic plaques.WSS is the frictional stress caused by blood flow and endothelial cell layer, which is consistent with the direction of blood flow and parallel to the long axis of blood vessels.

Many studies on local hemodynamics have also introduced another important parameter, the Oscillatory shear index (OSI), which is calculated by the following formula:

OSI is used to reflect the degree of direction change of WSS within a single cardiac cycle.The range of this value is generally 0-0.5.The closer the OSI value is to 0, the more stable the blood flow in the vessel is; otherwise, the blood flow is in a highly oscillating state.Time-averaged WSS (TAWSS) refers to the integral mean value of wall shear force in a period of time.In the study of atherosclerotic plaques, TAWSS was obtained by integrating the wall shear force at each time point in a cardiac cycle.Its calculation formula is as follows:

The distribution characteristics of mean wall shear force on vascular wall in a single cardiac cycle can be analyzed by TAWSS calculation.

Based on the WSS and OSI values, relative residence Time (RRT)was proposed in some studies.Its calculation formula is as follows:

RRT describes the residence time of a unit of blood particles in contact with or close to endothelial cells during a cardiac cycle.This parameter can be used to study the role of LDL distribution in the development of atherosclerosis.

The expression of the role of WSS in blood vessels is also multidirectional.Since different reference directions can be selected when quantifying this feature, two parameters have been proposed to illustrate this feature in recent years.Peiffer V et al.proposed horizontal WSS based on TAWSS direction, that is, the time average value of WSS component perpendicular to the average flow direction[8].The other is the axial WSS proposed by Morbiducci U et al.Which illustrates the time average value of WSS components parallel to the direction of blood flow within a cardiac cycle[9].The expression parameters of the two directions can produce the same effect when the blood flow direction remains the same, but they will show different values when the blood flow is separated, turbulent and oscillating[10].Gallo et al.[10] found that in blood vessels with carotid plaque formation, there were not only high lateral WSS regions, but also low WSS and high OSI regions, and these regions did not coincide, which meant that these parameters explaining WSS multipolarity could express different blood flow disorders in the bleeding canal.However, the effect of this parameter on carotid atherosclerosis remains to be further studied.

2.2.2 Local hemodynamics and vascular geometry related parameters in carotid atherosclerotic plaques

Position specificity of carotid artery atheromatous plaque formation geometry affects blood vessels make people found in the changes of local blood flow state, so the researchers on the study of the local blood flow dynamics related mechanical parameters at the same time, the study of vascular geometry parameters also have important significance, and this requires that people need to grasp the vascular geometry details.In the last decade, advances in imaging techniques have made it possible to quantify the geometric features of blood vessels, and subsequently researchers have found correlations between these geometric parameters and blood flow parameters.Lee et al.[11] measured and defined some vascular geometric parameters such as: Flatness, branch bending and the area of the internal carotid artery and external carotid artery combined ratio of area of common carotid arteries, and the turbulent flow within the carotid artery quantitative is exposed to the objective defined below threshold low oscillation shear endothelial surface area, research shows that intravascular low and shocks WSS turbulent area and the area ratio and there is a significant relationship between branch bending.Domanin[12] put forward, such as the carotid sinus and area ratio of the common carotid artery and radius ratio, three of the common carotid artery bifurcation sinuosity peacekeeping plane geometric parameters of the four blood vessels, the first two parameters are used to represent the carotid sinus surgery postoperative relative expanding degree, the study found that the expansion of the carotid sinus levels associated with the area of intravascular low WSS area.Azar et al.[13]retrospectively analyzed 50 diseased carotid arteries with a stenosis degree of 67.4% to 99.1% by means of numerical simulation, and proposed a number of vascular geometric related parameters such as lumen concave degree, curvature degree and mean area slope at the proximal and distal ends of plaque.The correlation between these parameters and other hemoflow-related mechanical parameters, such as TAWSS, OSI and RRT, was established.It was found that TAWSS increased with the increase of stenosis degree and mean area slope.It can be seen from the above studies that, through the hemodynamic analysis, the correlation and prediction model can be established between the hemodynamic mechanical parameters of the diseased carotid artery and the vascular geometric correlation parameters, so as to guide the clinical surgical decision-making.

3.Effect of local hemodynamics on carotid atherosclerotic plaque

3.1 The influence of local hemodynamics on the development of carotid atherosclerotic plaque

Exist in common carotid artery bifurcation carotid sinus a swollen oval vascular structures, the region’s unique vascular geometry make blood flow in the formation of the flow separation and turbulence,which leads to low WSS and shock WSS in the form[14], and previous research has found that low WSS and high OSI is the one important factor for the formation of carotid atherosclerosis[15].At the molecular level, Low WSS can induce junctional adhesion molecule-A (JAM-A) and vascular cell adhesion molecule-1(VCAM-1) and platelet-derived growth factor-a (PDGF-A) promote carotid atherosclerosis[16],At the same time, the expression of vascular protective factors such as nitric oxide is inhibited[17], so that monocytes can migrate into the intima through adhesion molecules to engulf lipids in the early stage of arteriosclerosis, and at the same time enhance the adhesion of platelets and white blood cells to the endothelial surface, thus intensifying the immune response of the body to lipid deposition.Vascular endothelial cells, on the other hand, the shape and arrangement of low WSS higher OSI and high sensitivity, the blood flow faster, WSS is high and flat area, vascular endothelial cells for spindle and closely packed, the distribution of the high and low in WSS and OSI area, endothelial cells to the circular structure, increase the gaps between the cells, increased vascular permeability, Low density lipoprotein and other substances are easy to penetrate into the arterial wall, resulting in lipid deposition and formation of atherosclerotic plaques[18].Therefore,endothelial cells can adjust accordingly with the change of WSS value and direction.In general model research, to spend 3 boss pig[19] and others on high fat feed for eight months, and home pig line left internal carotid artery intima destructive surgery induced carotid atherosclerotic plaques, then respectively 4, 6, 8 months after surgery to carotid plaques in pig and pathological biopsy for MRA scan,The internal carotid artery model was established through numerical simulation and hemodynamic analysis.It was found that there were strong inflammatory reactions and intimal thickening in the region with low WSS.Wang J et al.[20] constructed in vitro models of normal carotid artery and carotid artery with plaque, and artificially removed the plaque in the latter.Through comparison, they found that there were high OSI and high RRT regions at the bifurcation of the carotid artery model with plaque removal, and inferred that high OSI and high RRT promoted the formation of atherosclerotic plaques.

3.2 Influence of local hemodynamics on the progression of carotid atherosclerotic plaque

Low WSS and high OSI induced the formation of CAS plaque, and plaque protrusion in the lumen changed the geometry of the vascular structure, forming a new situation, resulting in further changes in the local hemodynamics of the vascular.In terms of the growth range of plaque, Steinman et al.[21] believed that WSS increased at the stenosis from the top of plaque to the wall, but low WSS and high OSI regions were formed at the distal end of the downstream of blood flow, and vascular endothelial was in the low WSS and high OSI regions, which stimulated the formation of new plaques.At the same time, the same area forms downstream of the new plaque, and this influence gradually leads to the formation of tandem plaques in the lumen.Wang J et al.[22] performed local hemodynamic analysis of the surrounding area of the tandem plaque in a patient with unilateral carotid artery tandem plaque formation using fluidstructure coupling method combined with numerical simulation, and found the existence of low WSS and high OSI regions downstream of the plaque and between the two plaques.It is speculated that the two tandem patches will then progress towards the region and gradually form a larger patch.

3.3 Effect of local hemodynamics on carotid atherosclerotic plaque rupture

At present, the measurement of plaque stenosis degree can no longer be used to evaluate the vulnerability and risk of plaque, and the local hemodynamic characteristics, components and morphology of plaque also interact with each other and affect the vulnerability of plaque.Histopathologically, vulnerable plaques are characterized by extensive inflammatory cell infiltration, intraplaque hemorrhage,intraplaque neovascularization, a thin fibrous cap (thickness < 65 μm), and a large lipid/necrotic core (greater than 40% of the total plaque volume).With the progression of plaque, the hemodynamic characteristics changed, and the blood flow velocity and WSS at the lumen stenosis increased continuously.Joo Myung Lee et al.[23] used CTA and CFD to perform local dynamic analysis on 66 ruptured plaques and found that WSS in the upstream of the ruptured plaque was significantly higher than that in the control group, and a number of studies showed that WSS value at the site of plaque rupture was abnormal[24], which was mostly located at the shoulder of the plaque.In addition, it is generally believed that intra-plaque bleeding increases the risk of plaque rupture.In local hemodynamic studies with intra-plaque bleeding, Dai et al.[25] studied the correlation between plaque stenosis degree and Intraplaque hemorrhage (IPH)based on MRI images and CFD, and found that when the stenosis degree is less than 70%, WSS is positively correlated with IPH volume.The mean WSS of IPH group was higher than that of non-IPH group.And the other from the perspective of molecular biology, high WSS can be induced by the molecular mechanisms of endothelial cells to make patchs vulnerable components form, such as WSS narrow area is higher than the normal range, will inhibit the protein synthesis of vascular smooth muscle cells, reduce platelet derived growth factor, cell apoptosis, and ultimately increase plaque ulnerability[26].

In terms of local hemodynamics, the essence of plaque rupture is that the stress on plaque reaches the stress limit of its structure, and the stress generated by blood flow on plaque exceeds the stress that the fibrous cap of plaque can carry, and the fibrous cap breaks and the plaque ruptures.Therefore, in addition to WSS, plaque structural stress (PSS) also plays an important role in the local hemodynamic factors of plaque rupture.When PSS is higher than the fiber cap tolerance limit, plaque rupture can occur.PSS is the circumferential stress generated in vascular wall and plaque when vasomotor occurs due to blood pressure.To a certain extent, it reflects the maximum elasticity and deformation ability of plaque under stress.In addition to blood pressure, the size of PSS is also affected by plaque structure and composition.Long et al.[27] reconstructed the plaque model in the pre-rupture state based on MRI images of three patients, and found that the PSS at the site of plaque rupture was significantly higher than that elsewhere through fluid-structure coupling stress analysis of the model.Stress concentration was found in all these patch models, and with the thickening of the fibrous cap, the local stress concentration shifted from the patch center to the shoulder.This is consistent with previous findings that plaque rupture is mostly located in the shoulder of plaque.In addition, microcalcification (μCalcs) affects plaque PSS.LI et al.[28] observed the stress distribution of arterial plaques in 3 patients with carotid atherosclerosis, and found that the plaque with calcium deposits confined to the thin fibrous cap of plaque increased PSS by 47.5% compared with the plaque without calcium deposits.Further,“spotty” μCalcs on the surface are associated with an increased risk of plaque rupture[29-30], However,μCalcs affect the occurrence of plaque rupture through stress concentration.Maldonado et al.[31]found a large number of μCalcs in the lipid core of 92 atheroscladeproducing arteries through high-resolution computed tomography,but these μCalcs did not increase the risk of plaque rupture.In addition, μCalcs were also observed in the fibrous cap of 9 plaques.After stress analysis, it was found that when μCalcs were located in the fibrous cap, stress concentration occurred, which significantly increased the PSS of the fibrous cap.When μCalcs were closely separated, PSS increased five times, which greatly increased the risk of plaque rupture.

4.Application of local hemodynamic study on carotid atherosclerotic plaque in clinical treatment

For the clinical treatment of moderate and severe Carotid atherosclerotic plaque, in addition to drug therapy, Carotid endarterectomy (CEA) and Carotid artery stenting (CAS) have been widely carried out clinically, and achieved good efficacy.The geometric morphology of carotid artery vessels after CEA and CAS changes, and the hemodynamics will also change accordingly.At present, the effectiveness of CAS and CEA is mainly judged by the measurement of lumen changes in imaging examination or the reduction of cerebrovascular events in follow-up evaluation.In order to better understand the mechanism of restenosis after revascularization.It is also important to study and monitor local hemodynamic changes after intervention.Dai et al.[32] studied the local hemodynamic characteristics after CEA through magnetic resonance angiography (MRA) and CFD.The results showed that compared with before CEA, the blood flow velocity, WS,WSSmean, WSSG and WSSmax in plaque stenosis after CEA decreased by 87.24%13.38%, 86.86%14.97%, 57.32%56.71% and 69.74%37.03%, respectively, while WSSmin remained basically unchanged.The ICA/ CCA flow rate ratio increased significantly after CEA.The study also found that the blood flow conditions after CEA were positively reconstructed to approximate the conditions of normal arteries.Domanin et al.[12] explored the prediction potential of hemodynamic barriers and postoperative carotid artery geometric features for long-term carotid artery restenosis after carotid endarterectomy (CEA), and believed that carotid artery repair should avoid widening of carotid artery ball diameter, which is related to restenosis caused by blood flow barriers.In addition,Chiu et al.[33] used Computational fluid dynamics (CFD) to study the local hemodynamics of carotid artery after CAS, and found that stent implantation into the vessel would change the distribution of OSI and WSS.Influence the occurrence and development of atherosclerotic plaque.Claudio Chiastra et al.[34] used optical coherence tomography (OCT) to model the bifurcation of patients’coronary arteries and then performed CFD analysis to quantify the different local hemodynamic effects of different types of stent implantation.Therefore, it provides theoretical basis for preventing restenosis after stent implantation.J.Garcia et al.[35] constructed an ideal finite element model of vascular bifurcation segment,numerically simulated the changes of hemodynamic parameters caused by stent placement at different positions in blood vessels, and experimentally verified the results with particle imaging velocimetry technology.Fan et al.[36] constructed patient-specific carotid artery models for two types of plaque (lipid plaque and calcified plaque)based on MRI images, and conducted numerical comparison of three stent implantation schemes of different lengths from the perspective of stress distribution.It was found that shorter stents were more likely to cause distal hemodynamic changes of stents.This change is not conducive to the prognosis of patients after CAS.Therefore,the above studies indicate that the study of postoperative local hemodynamics of carotid arteries in CEA and CAS patients can provide a basis for the selection of preoperative surgical methods,guide the details of intraoperative operation, and predict and avoid the occurrence of postoperative restenosis and other related complications.

5.Limitations and prospects of local hemodynamic study of carotid atherosclerotic plaque

In conclusion, local hemodynamic factors play an important role in the occurrence, progression and rupture of carotid atherosclerotic plaque.At home and abroad about local hemodynamics of carotid atherosclerotic plaques that medical professionals cross class research is still in the foundation stage, is on the basis of based on radiographic image or construction in vitro by using the computer numerical simulation model of the blood flow in the form of dynamic analysis, the institute will create an ideal model with elastic properties of blood vessels as a rigid pipe, The perception of blood containing cells and various biological molecules as a simpler Newtonian fluid is not consistent with the reality of the carotid artery in the body.Secondly, due to the limited imaging resolution of imaging technology, the extraction of carotid plaque and local carotid artery geometric structure, morphology and surface characteristics still needs to be further improved and detailed.In addition, due to the time consuming and certain technical requirements of numerical simulation analysis and in vitro model establishment, it is not enough to be popularized and normalized in daily clinical practice,and the sample selection of most studies is small.Although the current research results of mechanical parameters still have regular distribution, the above shortcomings may lead to some deviation from the real situation.

In the future, for the local hemodynamics of carotid atherosclerotic plaques, it is necessary to further improve the detail resolution of imaging technology and construct a model that can comprehensively consider the fluid-structure interaction, vascular wall elasticity,blood non-Newtonian characteristics and cardiac cycle.Researchers can carry out quantitative correlation prediction and comparative analysis between local mechanical parameters of carotid plaque and plaque composition and structure, and establish multi-parameter individualized model, providing more comprehensive factors for disease assessment and prediction of plaque rupture.