ReviewRole of hemodynamic shear stress in cardiovascular disease
Introduction
Cardiac, cerebral and peripheral localizations of atherosclerosis are the leading causes of morbidity and mortality in the Western world. Several systemic risk factors (environmental, genetic, and biological) contribute to the occurrence and progression of atherosclerotic processes [1], [2], [3], [4]. Although these risk factors predispose to its development, atherosclerosis usually involves specific vascular districts [5]. Recently, blood flow/shear has generated considerable interest as complementary explanation for plaque formation [6], [7]. The role of blood flow in atherosclerosis is based upon the observation that vascular inflammation and plaques are distributed at near side branches or arterial stenoses, where blood flow is nonuniform, and at the lesser curvature of bends where blood flow rate is relatively low. Blood flow exerts shear stress on the vessel wall by altering cell physiology via several mechanisms. Shear stress (τ), measured in N/m2 or Pascal (Pa), arises from the friction between two virtual layers in a fluid and is induced by the difference in movement of the two layers (; in case of a cylindrical tube) and the “roughness” (or viscosity Pa·s) between these layers (). Shear stress also arises at the interplay between blood and endothelial layer where it induces a shearing deformation of the endothelial cells. Regions of the arterial tree with uniform geometry are exposed to an undisturbed, unidirectional flow, which exerts a physiologic shear stress, whereas arches and branches are exposed to a disturbed, oscillatory flow, which exerts low shear. Atherosclerotic lesions occur predominantly at sites of low shear, whereas regions of the vasculature exposed to a physiologic shear are protected [8]. Low shear stress conditions can also occur both downstream and upstream of an obstruction [9]. In fact, a developing plaque can modify the local shear stress milieu in specific parts of and adjacent to the lesion. Lumen narrowing can result in increased flow velocity at the throat of the plaque, low shear stress in the upstream region, and disturbed flow in the form of directionally oscillatory shear stress in the downstream shoulder of the plaque (Fig. 1). These local shear stress conditions promote the formation of a rupture-prone plaque phenotype upstream of the lesion and additional growth downstream of the plaque [9].
In vitro and in vivo studies show that disturbed or oscillatory flows near arterial bifurcations, branch ostia, and curvatures are associated with atheroma formation [7] and intimal wall thickening [10], [11], [12], [13], [14]. Oscillatory flow is characterized by time-averaged fluctuations in shear stress during the cardiac cycle that are very low due to forward–reverse flow cycles and disrupted flows. This flow pattern exhibits regions of flow separation, recirculation and reattachment that are associated with temporal and spatial shear gradients [15].
Low and oscillatory shear stress are major features of the hemodynamic environment of sites opposite to arterial flow dividers that are predisposed to atherosclerosis [16]. In particular, oscillatory shear stress occurs primarily downstream of stenoses (Fig. 1), at the lateral walls of bifurcations, and in the vicinity of branch points [12], [17], [18], [19]. Beside the temporal oscillations, shear stress shows significant spatial oscillations over short distances, especially in geometrically irregular regions, resulting in high spatial gradients [19], [20], [21], [22].
Although low and oscillatory shear stress are closely associated with atherogenesis, the importance of these two different patterns is unclear. Even though different vascular territories (e.g., femoral, carotid and coronary arteries) might respond to various stimuli of wall shear stress differently [23], the occurrence of atherosclerotic lesions in the human carotid bifurcation and the abdominal aorta strongly correlates with low shear regions experiencing an almost purely oscillatory flow [12], [24].
Low and oscillatory shear stress as well as disrupted and turbulent flows are able to reduce nitric oxide production and to induce proinflammatory mediators synthesis through the following processes: NF-kB-dependent transcription, circulating monocytes recruitment, impaired flow regulated vasorelaxation and reversal of the antiapoptotic, antiproliferative and antioxidative functions of the endothelium [7].
By contrast, a physiologic shear protects against atherogenesis via a tri-molecular complex expressed on endothelial cells [25] and other mechano-sensory receptors able to convert mechanical forces into numerous biochemical signals by influencing lipid permeability, inhibition of the cell cycle, suppression of pro-thrombotic tissue factor activity [7] as well as anti-inflammatory activation of endothelial cells [8], [26], [27], [28], [29]. This latter effect is associated with inhibition of JNK and p38 MAP kinase signalling [26], [30] and alteration of NF-kB activity and function [28], [29], [31]. Thus, a physiologic laminar shear stress protects arteries from atherosclerosis by modulating the activities of pro-inflammatory MAP kinase and NF-kB signalling pathways in endothelial cells.
The methods for in vivo estimation of wall shear stress without sophisticated calculations are based on the Hagen–Poiseuille formula (τ = 4μQ/πR3, where τ is shear stress, μ the dynamic viscosity of blood, Q the volume flow-rate and R the inner radius of the conduit cylindrical tube), which requires the measurement of the blood volume flow rate as well as the radius of the vessel lumen at a specific site. Shear rate can be expressed in terms of average or maximum velocity. Thus, the measurement of the vessel radius and either the average or the maximum flow velocity is required for estimating wall shear stress. There are three methods to measure blood velocity in a vessel: non-invasive, invasive or through simulation by using computational fluid dynamics. Among non-invasive methods, two main techniques are available: ultrasound, in particular by pulsed Doppler, and magnetic resonance imaging phase contrast velocity mapping techniques. Two main invasive methods are available for measuring velocity patterns: intravascular ultrasound, with or without Doppler method application, and computational fluid dynamics, a term used to describe the body of knowledge and methods that seek the numerical solution of the governing equation of fluid flow. Usually, this latter technique consists in simulating flow patterns in a given geometry (with precise velocity and pressure distribution) subjected to certain boundary conditions for the flow variables [32].
Another invasive method, used in particular to measure hemodynamic shear stress in coronary arteries, consists in accurate 3-D reconstruction of vessel volume using intravascular ultrasound images and biplane coronary angiography. By this method the time required by the wave front of opacified blood, during coronary angiography, to go from the origin to the end of the 3-D reconstructed volume is also measured. Computational fluid dynamics techniques are then applied using the calculated flow within the reconstructed arterial volume [33].
This review will deal with the role of shear stress as possible mechanism involved in the development of atherosclerotic lesions in different vascular districts such as coronary, carotid, femoral arteries and aorta.
Section snippets
Hemodynamic shear stress and coronary atherosclerosis
Several studies demonstrated that atherosclerotic lesions are more frequent in the proximal portions of the three major coronary arteries than in the distal segments and in their branches [34], [35]; in particular, in patients with ST-elevation myocardial infarction coronary occlusion tends to cluster within the proximal third of all the three coronaries [36]. In these studies the prevalence of atherosclerosis in the two major branches of the left coronary artery was analyzed and a clustering
Hemodynamic shear stress and cerebrovascular atherosclerosis
The localization of carotid atherosclerosis is favoured by hemodynamic forces of wall shear stress and circumferential wall tension, respectively the frictional and the perpendicular forces of blood flowing on the vascular wall. In particular, in the carotid circulation there are specific areas where atherosclerosis preferentially occurs, such as the outer wall of the internal carotid artery [12], [13]; moreover, an interindividual variability in the development of atherosclerotic lesions in
Hemodynamic shear stress and cerebral aneurysms
The role of hemodynamic shear stress has been also analyzed in relation to the occurrence of intracranial aneurysms [73]. The localization of saccular aneurysms, which represents about 90% of cerebral aneurysms, is remarkably stable; in fact, most of them are located in the circle of Willis, in particular at arterial bifurcations or at the branching points [74], [75], [76]. Less commonly, aneurysms can appear on arterial curvatures, where they usually form on the outer curve [74]. Saccular
Hemodynamic shear stress and aorto-femoral atherosclerosis
The distribution and severity of atherosclerosis in the abdominal aorta preferentially involves the posterior wall of the infrarenal abdominal aorta, in which lower wall shear stress values are present [95] with flow alterations at this level: this phenomenon has been ascribed to the fact that branches along the anterior wall of aorta pull a significant amount of fluid away from the posterior wall, so creating a region of relatively low flow at that site [96]. At the aortic bifurcation two
Experimental studies on hemodynamic shear stress and atherosclerotic disease
Several experimental studies contributed to deepen our knowledge about the association between atherosclerotic disease and hemodynamic shear stress; in particular, a relevant contribution has been provided by animal studies performed in different arterial districts. Moreover, experimental studies largely concurred to clarify the biomolecular mechanisms linking oscillating and low shear stress with inflammation.
In animal models, high levels of NF-kB molecules have been detected in endothelial
Conclusions
The relevance of low or oscillatory wall shear stress in determining an increased risk of developing atherosclerotic lesions is largely documented in the arteries of both coronary and extracoronary district. Alterations in blood flow together with biomolecular changes of endothelial cells contribute to the focal distribution of atherosclerotic lesions and might be used to address new therapeutic strategies. The variations in local endothelial shear stress could also be useful to evaluate the
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