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New insights in atherosclerosis: Endothelial shear stress as promoter rather than initiator
Medical Hypotheses 73 (2009) 989–993
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
New insights in atherosclerosis: Endothelial shear stress as promoter rather than initiator Alireza Mehdizadeh a,*, Amir Norouzpour b a b
Department of Medical physics, School of Medicine, Shiraz University of Medical Sciences (SUMS), Shiraz, Iran Vascular Surgery Research Center, Imam Reza Hospital, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran
a r t i c l e
i n f o
Article history: Received 1 November 2008 Accepted 5 November 2008
s u m m a r y The etiology of focal distribution of atherosclerotic lesions has received much attention for many years. Current theories focus on mechanical factors such as low endothelial shear stress as an initiating factor for atherosclerosis formation. However, some evidences revealed that it could not be initiator of endothelial damage. We hypothesize that endothelial damage results from the fatigue effect of pulse pressure on endothelial layer. In our model, heart rate, magnitude of pulse pressure, geometry and chemical environment of endothelial layer determine the rate of endothelial damage accumulation, and low endothelial shear stress acts as promoter of atherosclerosis rather than initiator. If this model is correct, it can provide a framework for speculating about the risk of endothelial stress rupture in the population as a whole and in patients undergone arterial grafting procedures, and how this might be reduced. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction An integrated model for topographic distribution of atherosclerotic lesions in an individual has been taking into account for many years. Despite the entire vasculature is exposed to the systemic risk factors (e.g., diabetes mellitus, hypercholesterolemia, cigarette smoking), atherosclerosis develops at specific sites [1]. The propensity for atherosclerosis at bifurcations, branchings, and curvatures has led to conjectures that local mechanical factors such as endothelial shear stress potentiate atherogenesis. Mechanical risk factors Endothelial shear stress Endothelial shear stress (ESS) is the tangential force acts on the unit area of the endothelial layer which resists against blood flow. It is expressed in force/unit area (dyn/cm2) (Table 1) [2]. ESS is directly proportional to the blood viscosity (l), and the shear rate at the wall (dv/ds) (Fig. 1) [3]. Thus
Endothelial shear stress ¼ l shear rate Low ESS is expressed as non-oscillatory and oscillatory ESS. Low non-oscillatory ESS refers to ESS that is unidirectional at any given point but has a periodically fluctuating magnitude that results in significantly low time-average (approximately <10–20 dyn/cm2) [4]. It typically occurs at the inner areas of curvatures as well as up* Corresponding author. Tel./fax: +98 711 234 9332. E-mail address: [email protected] (A. Mehdizadeh). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.11.049
stream of stenoses [5]. Oscillatory ESS characterizes by significant changes in both directions (bidirectional) and magnitude between systole and diastole, resulting in very low time-average, usually close to zero [4]. It occurs primarily downstream of stenoses, at the lateral wall of bifurcations and in the vicinity of branch points [5,6]. Broadly accepted today, the focal distribution of atherosclerosis may be attributed to low endothelial shear stress (ESS) at susceptible regions. Many studies have revealed that low ESS is associated with the localization of atherosclerosis [7,8]. However, some evidences remain to be elucidated by regarding low ESS as the initiating factor of atherosclerosis. If low ESS is considered as the initiator of atherosclerosis, it would be expected that regions with physiologic ESS remain relatively free of atherosclerosis, but investigations have shown that some quiescent plaques develop in spite of physiologic ESS at baseline [9,10]. Additionally, some early atheromas evolve either stenotic or high-risk plaques. In evolution of early atheromas to stenotic plaques, low ESS does not appear to play a key role [9,10]. Also, comparing baseline ESS of high-risk plaque-prone regions with quiescent plaque-prone regions revealed that there is no significant difference between their baseline ESS [9–11]. Tensile stress In addition to ESS, tensile stress (TS), derived from hydrostatic blood pressure, is also applied on the vessel wall (Fig. 1). In the arterial system, mural TS fluctuates between two limits because of pulsatile nature of arterial blood pressure. Upper and lower limits of TS fluctuations are determined by maximum and minimum
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Table 1 Terminology. Stress The force acing on a surface divide by the cross-sectional area over which the force acts. It is expressed in dyn/cm2. Tensile stress A component of stress which acts circumferentially or longitudinally on a unit of length perpendicular to the direction of force. Ultimate strength The maximum stress a material can withstand when subjected to stress. It is the maximum stress on the stress–strain curve. Endothelial shear stress The tangential force acts on unit area of endothelial layer which resists against blood flow. Endothelial tensile stress The stress which acts circumferentially on the endothelial layer. It is derived from hydrostatic blood pressure. Mechanical fatigue In materials science, fatigue is the progressive and localized structural damage that occurs when a material is subjected to cyclic loading.
Fig. 1. The major hemodynamic forces include flow-derived shear stress (SS) and blood pressure-derived tensile stress (TS) imposed tangentially and circumferentially, respectively, on the arterial wall (SS = l. dv/ds; dv/ds = shear rate at the wall, l = blood viscosity, P = blood pressure, r = lumen radius, t = wall thickness).
of blood pressure, respectively, in each segment of the arterial tree. Thus, two main components of TS can be distinguished: One which is steady, results from minimal blood pressure in each segment of the arterial tree, and the other, which is unsteady (cyclic), results from fluctuation of blood pressure between a maximum and a minimum in that segment. The difference between maximal and minimal blood pressure in each segment is defined as the pulse pressure (PP). Thus, cyclic TS is derived from PP. Magnitude of mural cyclic TS is dependent on the amplitude of PP. Moreover, it is dependent on luminal radius, thickness and elastic properties of the vessel wall and external support of the vessel. The number of stress cycles is equal to the heart rate. Therefore, because of cyclic nature of TS, it could have a fatigue effect on the endothelial layer. Mechanical fatigue In materials science, fatigue is the progressive and localized structural damage that occurs when a material is subjected to cyclic loading. In this repetitive loading condition and damage accumulation, eventually fatigue failure (breakage) occurs while stress levels are much lower than those needed to produce failure following a single maximal load (i.e, the maximum stress values are less than the ultimate strength) (Table 1) [12]. Fatigue failure occurs in polymers, metals and other substances. Fatigue life is considered as the number of cycles before a material fails (it breaks). Fatigue life is dependent on different factors
such as the magnitude of cyclic stress, the geometry of materials, chemical environmental conditions and temperature. If the magnitude of cyclic stress increases, the fatigue life of the material decreases and the material breaks following fewer load cycles. Moreover, the geometry of materials determines stress distribution on them. Stress may be higher in some points called stress-concentration points. For example, the branch areas of pipe joints withstand higher intramural stress than their neighboring areas [13,14]. Mechanical fatigue damage is more likely to occur when and where the magnitude of cyclic load is higher. Fatigue damages begin to accumulate at points of stress-concentration until it finally results in fatigue failure. Chemical environment of materials can influence their structure and their microscopic geometry. It can cause erosion, corrosion, or gas-phase embrittlement, which all affect the fatigue life. Unlike materials in which damage is cumulative and materials are not repaired spontaneously when rested, in biologic systems, a tissue turns over continuously with different rates and thereby it under goes remodeling continuously. As a result, damages may be repaired not cumulated during a period of time. In addition, a tissue could be adapted to cyclic tensile stress by increasing its ultimate tensile strength to withstand the applied stress and prevent the mechanical damages. Since the processes of repair and adaptation are time-based, we consider the fatigue life as a time to failure rather than the number of cycles to failure, and whether fatigue failure occurs or not depends on the rate of fatigue damage accumulation and the rate of tissue repairing. The rate of fatigue
A. Mehdizadeh, A. Norouzpour / Medical Hypotheses 73 (2009) 989–993
damage accumulation is dependent on the frequency (number of cycles/period of time) and the magnitude of cyclic TS and the rate of adaptation. The concept of fatigue failure is applied to the design, manufacture and maintenance of aircraft, bridges, machinery and other objects exposed to cyclic loads. Moreover, in medicine, this concept has being formed a field of study in skeletal science [15], and in cardiovascular science [16,17].
Our proposed model In our model, penetration of blood atherogenic components into intima is through endothelial defects or ruptures. The ruptures are the result of fatigue failure of the endothelial layer caused by the fatigue effect of cyclic TS on the endothelial layer. Fatigue damage of the endothelial layer occurs throughout the life, and it is repaired continuously. The balance between the rate of fatigue damage accumulation and the rate of endothelial repairing determines that the fatigue failure of the endothelial layer occurs or not. At the early period of the life, the rate of endothelial repairing is high. Therefore, the fatigue damage may not accumulate rapidly, and repairing process limits the fatigue damage progression. On the other hand, the vessel wall is adapted to mural cyclic TS continuously. Thus, the ultimate tensile strength of its layers increases to withstand well the mural TS and prevent the tensile damages. However, the rate of adaptation and of endothelial repairing decreases with age. Thus, the endothelial layer is more susceptible to be damaged with age, and the rate of fatigue damage accumulation increases with age as a result of the decreased rate of adaptation. Also, fatigue failure of the endothelial layer occurs more rapidly as a result of the decreased rate of endothelial repairing with age. It means that over very long time periods, of the order of decades, the gradual decrease in the rate of adaptation results in an increasing risk of endothelial fatigue damage accumulation if the same cyclic TS remains. Also, the gradual decease in the rate of endothelial repairing results in an increasing risk of fatigue failure of the endothelial layer if the same cyclic TS remains. Blood atherogenic components could deposit into intima through the endothelial rupture until the ruptured endothelium is repaired. Moreover, after each episode of endothelial rupture, the geometry of intima and its overlying endothelium changes leading to changes in TS distribution on the endothelial layer. Therefore, it may result in arising new stress-concentration points on the endothelial layer leading to the increased rate of fatigue damage accumulation and fatigue failure at these regions. Thus, the frequency of fatigue failure of the endothelial layer increases exponentially with age leading to deposition of blood atherogenic components into intima in an episodic and exponentially increasing pattern. The fatigue effect of cyclic TS on the endothelial layer is determined by the magnitude and the frequency of cyclic TS, the geometry of endothelial layer and its chemical environment. These factors as well as the rate of adaptation determine the rate of fatigue damage accumulation. Whether fatigue failure of the endothelial layer occurs or not depends on the balance between the resultant rate of damage accumulation and the rate of endothelial repairing. The role of low ESS is considered as a factor which increases the residence time of atherogenic blood particles to deposit into intima. If ESS in ruptured sites of endothelial layer is lower, the rate of deposition of blood particles into intima through the ruptured sites is higher leading to progress atherosclerosis more rapidly at these regions. Thus, we consider the role of low ESS as promoter of atherosclerosis rather than initiator.
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Factors influencing the fatigue effect of cyclic TS Frequency of cyclic TS As the frequency of cyclic TS increases, the rate of damage accumulation increases. It is consistent with several large clinical studies shown that high heart rate, is associated with atherosclerosis, independently of other risk factors, such as age, gender, diabetes, hypertension and hyperlipidemia [18,19]. Experimental studies have also demonstrated that high heart rate is associated with atherosclerosis [20,21], whereas lowering of heart rate has reduced atherosclerosis [22,23]. Magnitude of cyclic TS As the magnitude of cyclic TS increases, endothelial layer is ruptured more rapidly. As mentioned above, the magnitude of cyclic TS is related to the amplitude of PP. Thus, in our model, each segment of the arterial tree which has higher amplitude of PP, is more susceptible to be atherosclerotic than other segments with lower amplitude of PP. Increases in the amplitude of PP from the arch of the aorta toward femoral arteries [24], due to reflection of pulse waves from arterial bifurcations and resistant arterioles, cause increase in atherosclerosis susceptibility correspondingly, whereas decreases in the amplitude of PP toward radial arteries result in decreased susceptibility in these regions. It could be supported by evidences showing that PP is an independent risk factor for atherosclerosis [25,26]. Investigations have shown that increases in arterial cyclic TS due to increased amplitude of PP have led to increases in the rate of endothelial damage accumulation and atherosclerosis formation [27,28]. In contrast, decreases in cyclic TS by decreasing the amplitude of PP [29,30], or considering pressure-bearing effects of surrounding tissues of the vessels (e.g., intramyocardial [15], vertebral [31] and hepatic [32] arteries), or placing external rigid supports around the vessels [33,34], have reduced atherogenic tendencies. It is interesting that other variables such as ESS [33,34] or heart rate [34] have not been altered when external supports have been placed. Moreover, some investigations indicated that the elevated amplitude of PP increases deposition of serum lipids and circulating proinflammatory molecules into intima [35], whereas the reduced amplitude of PP inhibits deposition of cholesterol and lipoproteins [36]. We may note that atherosclerosis do not develop in the veins in which blood pressure and endothelial TS is low, but the atherosclerotic lesions do develop when the veins are used as arterial bypass grafts where there are subjected to high cyclic TS. Geometry of vessels The geometry of vessels influences TS distribution on the endothelial layer and its fatigue life. In the arterial tree, TS in branch areas or bifurcations is greater than that in relatively straight segments [37]. In addition, it has been established that in the arterial curvature, TS is much higher on the inner than on the outer curve [38]. This is consistent with the observations that atherosclerotic lesions usually favor the inner curve or bifurcations [1]. Moreover, experiments on the aortic valve have revealed that atherosclerotic lesions form only in the area of maximum TS [39].
Chemical environment of the endothelial layer Chemical environment of the endothelial layer also influences its fatigue life, analogous to different microscopic structure of materials in different chemical environments. In our model,
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diabetes mellitus and smoking promote atherosclerosis formation via changing the normal structure of endothelial cells and accelerating the fatigue effect of cyclic TS. From this point of view, the roles of oxidative stress on endothelial damage and atherosclerosis formation could be modeled more precisely. Conclusion Fatigue failure of endothelial layer caused by cyclic TS is essential for atherosclerosis formation. Whether the fatigue failure of the endothelial layer occurs or not depends on the rate of fatigue damage accumulation and the rate of repairing. Repair can be modeled as a process which competes with damage accumulation. In addition, the rate of fatigue damage accumulation is determined by the factors influencing the fatigue effect of cyclic TS and the rate of vessel wall adaptation. By regarding TS and low ESS as the initiator and the promoter of atherosclerosis respectively, one could predict the topographic distribution of atherosclerotic lesions more precisely. Further experimental studies specifically directed at measuring time dependent changes in endothelial layer and intima during deposition of blood components and formation of atherosclerotic lesions will be necessary to test this theoretical model directly. Clinical implications If this model is correct, it can provide a framework for thinking about the risk of stress rupture in the population as a whole and how this might be reduced. Theoretical models could be developed to predict the effect that a change in the frequency and the magnitude of cyclic TS might have on the overall incidence of fatigue rupture of endothelial layer and atherosclerosis. As a result, treatment modalities should be directed to reduce the amplitude of PP and heart rate. Also, geometrical analysis of vessels could reveal their stress-concentration points. Regarding these points as well as low ESS regions help us to predict atherosclerosis-prone regions more precisely and to direct surgical procedures to prolong the endothelial fatigue life of these susceptible regions. It also could be applied to arterial bypass grafting procedures in which the geometry of the bypass grafts as well as the anastomoses could be changed to the most appropriate geometry with longer endothelial fatigue life. Conflict of Interest Statement The authors had no grant or funding source. Acknowledgements The authors gratefully thank Dr. Kazemzadeh from Vascular Surgery Research Center, Imam Reza Hospital. References [1] DeBakey ME, Lawrie GM, Glaeser DH. Patterns of atherosclerosis and their surgical significance. Ann Surg 1985;201(2):115–31. [2] Slager CJ, Wentzel JJ, Gijsen FJ, et al. The role of shear stress in the generation of rupture-prone vulnerable plaques. Nat Clin Pract Cardiovasc Med 2005;2:401–7. [3] Cokelet GR, Meiselman HJ, Brooks DE. Erythrocyte mechanics and blood flow. New York: A.R. Liss; 1980. [4] Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA 1999;282:2035–42. [5] Ku D. Blood flow in arteries. Annu Rev Fluid Mech 1997;79:399–434. [6] Soulis JV, Giannoglou GD, Chatzizisis YS, et al. Spatial and phasic oscillation of non-Newtonian wall shear stress in human left coronary artery bifurcation: an insight to atherogenesis. Coron Artery Dis 2006;17:351–8. [7] Moore Jr JE, Xu C, Glagov S, Zarins CK, Ku DN. Fluid wall shear stress measurements in a model of the human abdominal aorta: oscillatory behavior and relationship to atherosclerosis. Atherosclerosis 1994;110:225–40.
[8] Gnasso A, Carallo C, Irace C, et al. Association between intima-media thickness and wall shear stress in common carotid arteries in healthy male subjects. Circulation 1996;94(12):3257–62. [9] Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol 2007;49:2379–93. [10] Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Stone PH, Feldman CL. Risk stratification of individual coronary lesions using local endothelial shear stress: a new paradigm for managing coronary artery disease. Curr Opin Cardiol 2007;22:552–64. [11] Chatzizisis YS, Jonas M, Coskun AU, et al. Prediction of the localization of highrisk coronary atherosclerotic plaques on the basis of low endothelial shear stress. An intravascular ultrasound and histopathology natural history study. Circulation 2008;117:993–1002. [12] Callister WD. 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Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation 2008;117(18):2377–87. [24] McDonald DA. Blood flow in arteries. 2nd ed. Baltimore: Williams and Wilkins; 1974. [25] Witteman JCM, Grobbee DE, Valkenburg HA, van Hemert AM, Stijnen T, Hofman A. J-shaped relation between change in diastolic blood pressure and progression of aortic atherosclerosis. Lancet 1994;343:504–7. [26] Kannel WB, Wilson PW, Nam BH, D’Agostino RB, Li J. A likely explanation for the J-curve of blood pressure cardiovascular risk. Am J Cardiol 2004;94(3):380–4. [27] Roux SP, Kuhn H, Lengsfeld H, Morand OH. Effects of chronic aortic coarctation on atherosclerosis and arterial lipid accumulation in the Watanabe hereditary hyperlipidemic (WHHL) rabbit. Atherosclerosis 1992;93:123–32. [28] Stehbens WE. Experimental induction of atherosclerosis associated with femoral arteriovenous fistulae in rabbits on a stock diet. Atherosclerosis 1992;95:127–35. [29] Bomberger RA, Zarins CK, Taylor KE, Glagov S. Effect of hypotension on atherogenesis and aortic wall composition. J Surg Res 1980;28: 402–9. [30] Hollander W, Prusty S. The effect of the arterial pressure pulse on atherogenesis. In: Presented at the tenth Hugh Lofland conference on arterial wall metabolism, 1985, Boston. [31] Meyer WW. On the rhythmic localization of atherosclerotic foci in the cervical segment of the vertebral artery. Bertr Pathol Anat 1964;130:24–39. [32] Krus S, Turjman MW, Fiejka E. Comparative morphology of the hepatic and coronary artery walls. Part III. The insignificance of medial morphologic features in the determination of an autopsied unidentified subjects age. Med Sci Monit 2000;6(3):629–31. [33] Thubrikar MJ, Baker JW, Nolan SP. Inhibition of atherosclerosis associated with reduction of arterial intramural stress in rabbits. Arteriosclerosis 1988;8:410–20. [34] Tropea BI, Schwarzacher SP, Chang A, et al. Reduction of aortic wall motion inhibits hypertension mediated experimental atherosclerosis. Arterioscler Thromb Vasc Biol 2000;20:2127–33. [35] Kiefer CR, McKenney JB, Trainor JF, Michael Snyder L. Pulse pressure-driven neutral lipid accumulation and correlative proinflammatory markers of accelerated atherogenesis. Atherosclerosis 2005;183:17–24. [36] Deng X, Marois Y, Guidoin R, et al. Efficiency of an external support to reduce lipid infiltration into venous grafts: in vitro evaluation. Artif Organs 1996;20:1208–14.
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Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
New insights in atherosclerosis: Endothelial shear stress as promoter rather than initiator Alireza Mehdizadeh a,*, Amir Norouzpour b a b
Department of Medical physics, School of Medicine, Shiraz University of Medical Sciences (SUMS), Shiraz, Iran Vascular Surgery Research Center, Imam Reza Hospital, Mashhad University of Medical Sciences (MUMS), Mashhad, Iran
a r t i c l e
i n f o
Article history: Received 1 November 2008 Accepted 5 November 2008
s u m m a r y The etiology of focal distribution of atherosclerotic lesions has received much attention for many years. Current theories focus on mechanical factors such as low endothelial shear stress as an initiating factor for atherosclerosis formation. However, some evidences revealed that it could not be initiator of endothelial damage. We hypothesize that endothelial damage results from the fatigue effect of pulse pressure on endothelial layer. In our model, heart rate, magnitude of pulse pressure, geometry and chemical environment of endothelial layer determine the rate of endothelial damage accumulation, and low endothelial shear stress acts as promoter of atherosclerosis rather than initiator. If this model is correct, it can provide a framework for speculating about the risk of endothelial stress rupture in the population as a whole and in patients undergone arterial grafting procedures, and how this might be reduced. Ó 2009 Elsevier Ltd. All rights reserved.
Introduction An integrated model for topographic distribution of atherosclerotic lesions in an individual has been taking into account for many years. Despite the entire vasculature is exposed to the systemic risk factors (e.g., diabetes mellitus, hypercholesterolemia, cigarette smoking), atherosclerosis develops at specific sites [1]. The propensity for atherosclerosis at bifurcations, branchings, and curvatures has led to conjectures that local mechanical factors such as endothelial shear stress potentiate atherogenesis. Mechanical risk factors Endothelial shear stress Endothelial shear stress (ESS) is the tangential force acts on the unit area of the endothelial layer which resists against blood flow. It is expressed in force/unit area (dyn/cm2) (Table 1) [2]. ESS is directly proportional to the blood viscosity (l), and the shear rate at the wall (dv/ds) (Fig. 1) [3]. Thus
Endothelial shear stress ¼ l shear rate Low ESS is expressed as non-oscillatory and oscillatory ESS. Low non-oscillatory ESS refers to ESS that is unidirectional at any given point but has a periodically fluctuating magnitude that results in significantly low time-average (approximately <10–20 dyn/cm2) [4]. It typically occurs at the inner areas of curvatures as well as up* Corresponding author. Tel./fax: +98 711 234 9332. E-mail address: [email protected] (A. Mehdizadeh). 0306-9877/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.11.049
stream of stenoses [5]. Oscillatory ESS characterizes by significant changes in both directions (bidirectional) and magnitude between systole and diastole, resulting in very low time-average, usually close to zero [4]. It occurs primarily downstream of stenoses, at the lateral wall of bifurcations and in the vicinity of branch points [5,6]. Broadly accepted today, the focal distribution of atherosclerosis may be attributed to low endothelial shear stress (ESS) at susceptible regions. Many studies have revealed that low ESS is associated with the localization of atherosclerosis [7,8]. However, some evidences remain to be elucidated by regarding low ESS as the initiating factor of atherosclerosis. If low ESS is considered as the initiator of atherosclerosis, it would be expected that regions with physiologic ESS remain relatively free of atherosclerosis, but investigations have shown that some quiescent plaques develop in spite of physiologic ESS at baseline [9,10]. Additionally, some early atheromas evolve either stenotic or high-risk plaques. In evolution of early atheromas to stenotic plaques, low ESS does not appear to play a key role [9,10]. Also, comparing baseline ESS of high-risk plaque-prone regions with quiescent plaque-prone regions revealed that there is no significant difference between their baseline ESS [9–11]. Tensile stress In addition to ESS, tensile stress (TS), derived from hydrostatic blood pressure, is also applied on the vessel wall (Fig. 1). In the arterial system, mural TS fluctuates between two limits because of pulsatile nature of arterial blood pressure. Upper and lower limits of TS fluctuations are determined by maximum and minimum
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A. Mehdizadeh, A. Norouzpour / Medical Hypotheses 73 (2009) 989–993
Table 1 Terminology. Stress The force acing on a surface divide by the cross-sectional area over which the force acts. It is expressed in dyn/cm2. Tensile stress A component of stress which acts circumferentially or longitudinally on a unit of length perpendicular to the direction of force. Ultimate strength The maximum stress a material can withstand when subjected to stress. It is the maximum stress on the stress–strain curve. Endothelial shear stress The tangential force acts on unit area of endothelial layer which resists against blood flow. Endothelial tensile stress The stress which acts circumferentially on the endothelial layer. It is derived from hydrostatic blood pressure. Mechanical fatigue In materials science, fatigue is the progressive and localized structural damage that occurs when a material is subjected to cyclic loading.
Fig. 1. The major hemodynamic forces include flow-derived shear stress (SS) and blood pressure-derived tensile stress (TS) imposed tangentially and circumferentially, respectively, on the arterial wall (SS = l. dv/ds; dv/ds = shear rate at the wall, l = blood viscosity, P = blood pressure, r = lumen radius, t = wall thickness).
of blood pressure, respectively, in each segment of the arterial tree. Thus, two main components of TS can be distinguished: One which is steady, results from minimal blood pressure in each segment of the arterial tree, and the other, which is unsteady (cyclic), results from fluctuation of blood pressure between a maximum and a minimum in that segment. The difference between maximal and minimal blood pressure in each segment is defined as the pulse pressure (PP). Thus, cyclic TS is derived from PP. Magnitude of mural cyclic TS is dependent on the amplitude of PP. Moreover, it is dependent on luminal radius, thickness and elastic properties of the vessel wall and external support of the vessel. The number of stress cycles is equal to the heart rate. Therefore, because of cyclic nature of TS, it could have a fatigue effect on the endothelial layer. Mechanical fatigue In materials science, fatigue is the progressive and localized structural damage that occurs when a material is subjected to cyclic loading. In this repetitive loading condition and damage accumulation, eventually fatigue failure (breakage) occurs while stress levels are much lower than those needed to produce failure following a single maximal load (i.e, the maximum stress values are less than the ultimate strength) (Table 1) [12]. Fatigue failure occurs in polymers, metals and other substances. Fatigue life is considered as the number of cycles before a material fails (it breaks). Fatigue life is dependent on different factors
such as the magnitude of cyclic stress, the geometry of materials, chemical environmental conditions and temperature. If the magnitude of cyclic stress increases, the fatigue life of the material decreases and the material breaks following fewer load cycles. Moreover, the geometry of materials determines stress distribution on them. Stress may be higher in some points called stress-concentration points. For example, the branch areas of pipe joints withstand higher intramural stress than their neighboring areas [13,14]. Mechanical fatigue damage is more likely to occur when and where the magnitude of cyclic load is higher. Fatigue damages begin to accumulate at points of stress-concentration until it finally results in fatigue failure. Chemical environment of materials can influence their structure and their microscopic geometry. It can cause erosion, corrosion, or gas-phase embrittlement, which all affect the fatigue life. Unlike materials in which damage is cumulative and materials are not repaired spontaneously when rested, in biologic systems, a tissue turns over continuously with different rates and thereby it under goes remodeling continuously. As a result, damages may be repaired not cumulated during a period of time. In addition, a tissue could be adapted to cyclic tensile stress by increasing its ultimate tensile strength to withstand the applied stress and prevent the mechanical damages. Since the processes of repair and adaptation are time-based, we consider the fatigue life as a time to failure rather than the number of cycles to failure, and whether fatigue failure occurs or not depends on the rate of fatigue damage accumulation and the rate of tissue repairing. The rate of fatigue
A. Mehdizadeh, A. Norouzpour / Medical Hypotheses 73 (2009) 989–993
damage accumulation is dependent on the frequency (number of cycles/period of time) and the magnitude of cyclic TS and the rate of adaptation. The concept of fatigue failure is applied to the design, manufacture and maintenance of aircraft, bridges, machinery and other objects exposed to cyclic loads. Moreover, in medicine, this concept has being formed a field of study in skeletal science [15], and in cardiovascular science [16,17].
Our proposed model In our model, penetration of blood atherogenic components into intima is through endothelial defects or ruptures. The ruptures are the result of fatigue failure of the endothelial layer caused by the fatigue effect of cyclic TS on the endothelial layer. Fatigue damage of the endothelial layer occurs throughout the life, and it is repaired continuously. The balance between the rate of fatigue damage accumulation and the rate of endothelial repairing determines that the fatigue failure of the endothelial layer occurs or not. At the early period of the life, the rate of endothelial repairing is high. Therefore, the fatigue damage may not accumulate rapidly, and repairing process limits the fatigue damage progression. On the other hand, the vessel wall is adapted to mural cyclic TS continuously. Thus, the ultimate tensile strength of its layers increases to withstand well the mural TS and prevent the tensile damages. However, the rate of adaptation and of endothelial repairing decreases with age. Thus, the endothelial layer is more susceptible to be damaged with age, and the rate of fatigue damage accumulation increases with age as a result of the decreased rate of adaptation. Also, fatigue failure of the endothelial layer occurs more rapidly as a result of the decreased rate of endothelial repairing with age. It means that over very long time periods, of the order of decades, the gradual decrease in the rate of adaptation results in an increasing risk of endothelial fatigue damage accumulation if the same cyclic TS remains. Also, the gradual decease in the rate of endothelial repairing results in an increasing risk of fatigue failure of the endothelial layer if the same cyclic TS remains. Blood atherogenic components could deposit into intima through the endothelial rupture until the ruptured endothelium is repaired. Moreover, after each episode of endothelial rupture, the geometry of intima and its overlying endothelium changes leading to changes in TS distribution on the endothelial layer. Therefore, it may result in arising new stress-concentration points on the endothelial layer leading to the increased rate of fatigue damage accumulation and fatigue failure at these regions. Thus, the frequency of fatigue failure of the endothelial layer increases exponentially with age leading to deposition of blood atherogenic components into intima in an episodic and exponentially increasing pattern. The fatigue effect of cyclic TS on the endothelial layer is determined by the magnitude and the frequency of cyclic TS, the geometry of endothelial layer and its chemical environment. These factors as well as the rate of adaptation determine the rate of fatigue damage accumulation. Whether fatigue failure of the endothelial layer occurs or not depends on the balance between the resultant rate of damage accumulation and the rate of endothelial repairing. The role of low ESS is considered as a factor which increases the residence time of atherogenic blood particles to deposit into intima. If ESS in ruptured sites of endothelial layer is lower, the rate of deposition of blood particles into intima through the ruptured sites is higher leading to progress atherosclerosis more rapidly at these regions. Thus, we consider the role of low ESS as promoter of atherosclerosis rather than initiator.
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Factors influencing the fatigue effect of cyclic TS Frequency of cyclic TS As the frequency of cyclic TS increases, the rate of damage accumulation increases. It is consistent with several large clinical studies shown that high heart rate, is associated with atherosclerosis, independently of other risk factors, such as age, gender, diabetes, hypertension and hyperlipidemia [18,19]. Experimental studies have also demonstrated that high heart rate is associated with atherosclerosis [20,21], whereas lowering of heart rate has reduced atherosclerosis [22,23]. Magnitude of cyclic TS As the magnitude of cyclic TS increases, endothelial layer is ruptured more rapidly. As mentioned above, the magnitude of cyclic TS is related to the amplitude of PP. Thus, in our model, each segment of the arterial tree which has higher amplitude of PP, is more susceptible to be atherosclerotic than other segments with lower amplitude of PP. Increases in the amplitude of PP from the arch of the aorta toward femoral arteries [24], due to reflection of pulse waves from arterial bifurcations and resistant arterioles, cause increase in atherosclerosis susceptibility correspondingly, whereas decreases in the amplitude of PP toward radial arteries result in decreased susceptibility in these regions. It could be supported by evidences showing that PP is an independent risk factor for atherosclerosis [25,26]. Investigations have shown that increases in arterial cyclic TS due to increased amplitude of PP have led to increases in the rate of endothelial damage accumulation and atherosclerosis formation [27,28]. In contrast, decreases in cyclic TS by decreasing the amplitude of PP [29,30], or considering pressure-bearing effects of surrounding tissues of the vessels (e.g., intramyocardial [15], vertebral [31] and hepatic [32] arteries), or placing external rigid supports around the vessels [33,34], have reduced atherogenic tendencies. It is interesting that other variables such as ESS [33,34] or heart rate [34] have not been altered when external supports have been placed. Moreover, some investigations indicated that the elevated amplitude of PP increases deposition of serum lipids and circulating proinflammatory molecules into intima [35], whereas the reduced amplitude of PP inhibits deposition of cholesterol and lipoproteins [36]. We may note that atherosclerosis do not develop in the veins in which blood pressure and endothelial TS is low, but the atherosclerotic lesions do develop when the veins are used as arterial bypass grafts where there are subjected to high cyclic TS. Geometry of vessels The geometry of vessels influences TS distribution on the endothelial layer and its fatigue life. In the arterial tree, TS in branch areas or bifurcations is greater than that in relatively straight segments [37]. In addition, it has been established that in the arterial curvature, TS is much higher on the inner than on the outer curve [38]. This is consistent with the observations that atherosclerotic lesions usually favor the inner curve or bifurcations [1]. Moreover, experiments on the aortic valve have revealed that atherosclerotic lesions form only in the area of maximum TS [39].
Chemical environment of the endothelial layer Chemical environment of the endothelial layer also influences its fatigue life, analogous to different microscopic structure of materials in different chemical environments. In our model,
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diabetes mellitus and smoking promote atherosclerosis formation via changing the normal structure of endothelial cells and accelerating the fatigue effect of cyclic TS. From this point of view, the roles of oxidative stress on endothelial damage and atherosclerosis formation could be modeled more precisely. Conclusion Fatigue failure of endothelial layer caused by cyclic TS is essential for atherosclerosis formation. Whether the fatigue failure of the endothelial layer occurs or not depends on the rate of fatigue damage accumulation and the rate of repairing. Repair can be modeled as a process which competes with damage accumulation. In addition, the rate of fatigue damage accumulation is determined by the factors influencing the fatigue effect of cyclic TS and the rate of vessel wall adaptation. By regarding TS and low ESS as the initiator and the promoter of atherosclerosis respectively, one could predict the topographic distribution of atherosclerotic lesions more precisely. Further experimental studies specifically directed at measuring time dependent changes in endothelial layer and intima during deposition of blood components and formation of atherosclerotic lesions will be necessary to test this theoretical model directly. Clinical implications If this model is correct, it can provide a framework for thinking about the risk of stress rupture in the population as a whole and how this might be reduced. Theoretical models could be developed to predict the effect that a change in the frequency and the magnitude of cyclic TS might have on the overall incidence of fatigue rupture of endothelial layer and atherosclerosis. As a result, treatment modalities should be directed to reduce the amplitude of PP and heart rate. Also, geometrical analysis of vessels could reveal their stress-concentration points. Regarding these points as well as low ESS regions help us to predict atherosclerosis-prone regions more precisely and to direct surgical procedures to prolong the endothelial fatigue life of these susceptible regions. It also could be applied to arterial bypass grafting procedures in which the geometry of the bypass grafts as well as the anastomoses could be changed to the most appropriate geometry with longer endothelial fatigue life. Conflict of Interest Statement The authors had no grant or funding source. Acknowledgements The authors gratefully thank Dr. Kazemzadeh from Vascular Surgery Research Center, Imam Reza Hospital. References [1] DeBakey ME, Lawrie GM, Glaeser DH. Patterns of atherosclerosis and their surgical significance. Ann Surg 1985;201(2):115–31. [2] Slager CJ, Wentzel JJ, Gijsen FJ, et al. The role of shear stress in the generation of rupture-prone vulnerable plaques. Nat Clin Pract Cardiovasc Med 2005;2:401–7. [3] Cokelet GR, Meiselman HJ, Brooks DE. Erythrocyte mechanics and blood flow. New York: A.R. Liss; 1980. [4] Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA 1999;282:2035–42. [5] Ku D. Blood flow in arteries. Annu Rev Fluid Mech 1997;79:399–434. [6] Soulis JV, Giannoglou GD, Chatzizisis YS, et al. Spatial and phasic oscillation of non-Newtonian wall shear stress in human left coronary artery bifurcation: an insight to atherogenesis. Coron Artery Dis 2006;17:351–8. [7] Moore Jr JE, Xu C, Glagov S, Zarins CK, Ku DN. Fluid wall shear stress measurements in a model of the human abdominal aorta: oscillatory behavior and relationship to atherosclerosis. Atherosclerosis 1994;110:225–40.
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