- Email: [email protected]
Atherosclerosis and acute coronary syndromes
Cardiovascular Pathology 14 (2005) 181 – 184
Review Article
Atherosclerosis and acute coronary syndromesB Avrum I. GotliebT Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada Department of Pathology, University Health Network, Toronto, Canada Received 23 March 2005; accepted 30 March 2005
Abstract In the past 20 years, there has been much new knowledge discovered on the pathogenesis of atherosclerosis and complicated and vulnerable plaques leading to a better understanding of acute coronary syndromes (ACS). The role of thrombosis, lipid metabolism, and inflammation has been investigated at the cellular and molecular levels, resulting in important new diagnostic and therapeutic strategies. The characterization of the role of hemodynamic shear stress and its regulation of cytoskeletal function in endothelial repair and the discovery of endothelial precursor cells (EPCs) derived from the bone marrow have provided new insight into vascular repair. Thus, our knowledge continues to increase, leading to improved prevention, diagnosis, and treatment of ACS. D 2005 Elsevier Inc. All rights reserved. Keywords: Atherosclerosis; Acute coronary syndromes; Endothelium; Cytoskeleton; Hemodynamic shear stress; Vascular repair
1. Introduction
2. Atherosclerosis
Coronary artery disease is the leading cause of mortality in the western world [1]. Acute coronary syndromes (ACS) are characterized clinically into three groups: patients with unstable angina, those with non-ST elevation myocardial infarction (non-STEMI), and those with ST elevation myocardial infarction (STEMI). The three clinical conditions have similar pathophysiologies, although each has different clinical features, therapies, and prognosis. The presence of atherothrombotic coronary artery occlusion due to plaque rupture and superimposed thrombosis with or without distal embolization is the common pathophysiology of ACS. The extent of lumen occlusion and the role of vasospasm is variable, thus, patients with unstable angina may have nonocclusive thrombi, leading to reduced myocardial perfusion.
The lesions of atherosclerosis were identified by anatomical pathologists well before establishing a causal association between the histopathology observations found in arteries at autopsy and the clinical syndromes of coronary artery disease. Atherosclerosis has been shown to be present as far back as ancient Egypt (reviewed in Ref. [2]). Jean Lobstein used the term arteriosclerosis in an 1829 pathology monograph. Carl Rokitansky promoted a thrombogenic theory of atherosclerosis in 1852. Rudolf Virchow, in 1858, identified the presence of intimal deposits in arteries. He focused his thinking on cells, connective tissue, and ultimately on vascular degeneration [3]. By the first decade of the 20th century, both Alexander Ignatovski and Nikolai Anitschkov carried out experiments that showed that egg yolk and pure cholesterol caused atherosclerosis in experimental animals. The hypercholesterolemic model of atherogenesis became a well-studied model, in many species, and has now been successfully extended to transgenic murine models, including mouse models with features of advanced human atherosclerotic plaques and elements of plaque instability [4]. The development of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins, to treat hypercholesterolemia has had a profound
B This article is based on a presentation at the Society for Cardiovascular Pathology Companion Meeting at the United States and Canadian Academy of Pathology, February 27, 2005, San Antonio, TX. T Department of Laboratory Medicine and Pathobiology, Banting Institute, University of Toronto, Room 110, 100 College Street, Toronto, Canada ON M5G 1L5. Tel.: +1 416 978 2557; fax: +1 416 978 7361. E-mail address: [email protected].
1054-8807/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.carpath.2005.03.007
182
A.I. Gotlieb / Cardiovascular Pathology 14 (2005) 181–184
therapeutic affect on ACS, and the recent identification of the nonlipid effects of statins that target a variety of biologic processes involved in atherogenesis and plaque vulnerability is an important advancement [5]. Alongside these lipid studies, the role of thrombosis in atherogenesis was being well studied, improving the understanding of platelet structure and function and of coagulation and fibrinolytic processes [6,7]. Elegant, detailed morphological and clinical pathologic studies in the past 20 –30 years by anatomic pathologists provided very important new knowledge that helped to focus and design studies on pathogenesis [8–14]. The field of atherogenesis began to utilize innovative biochemical, cellular, and molecular investigations on human biologic material, experimental animal models, and in in vitro systems to direct attention to cell function, especially that of monocyte/macrophages, endothelial, and smooth muscle cells. The technologies that were being utilized included genomics, proteomics, imaging (static and live cell imaging to understand molecular events), clinical chemistry, and interdisciplinary approaches involving integrative biology, bioengineering, computational biology, regenerative medicine, biomaterials, and clinical imaging. Today, the intense study of endothelial and smooth muscle cell function, hemodynamic shear stress, lipid deposition, macrophage function and inflammation, immune activity, neovascularization, thrombosis, matrix remodeling, and fibrous cap rupture [1] has been made possible by the major advance of being able to culture pure vascular endothelial cells and smooth muscle cells, which was established in the late 1970s and early 1980s [15–18]. Investigations on the pathogenesis of atherosclerosis also led to a better understanding of the clinical conditions of ACS [9–14], especially in relation to the structure and function of the fibroinflammatory lipid plaque and its complications. Studies were now directed at the pathogenesis, diagnosis, risk stratification, and treatment using well-conceived clinical practice guidelines of ACS, especially as they relate to thrombosis, plaque rupture, and plaque growth. In addition, the contribution of genetic risk factors to the development of ACS is being very actively studied. Proinflammatory gene polymorphisms have now become an important area of study to understand the development of atheromatous plaque vulnerability [19]. Two major outstanding questions will benefit from ongoing state-of-the-art research studies. The questions are why the thrombotic response in the lumen is not necessarily associated with the extent of the rupture in individual patients and why is it that angiographically identified minor to moderate plaques do rupture. Answers to these issues will identify important biologic processes that may be targeted to prevent and/or treat ACS. Novel transgenic mouse models, recently identified and characterized, that have complicated atherosclerotic plaques with characteristics similar to human vulnerable plaques are likely to become an important model to study plaque rupture [20,21].
3. The endothelium, integrator of normal and abnormal vascular biology The endothelium functions as a permeability barrier, a thromboresistant surface, and as an initiator and/or inhibitor of numerous biologic processes, especially those related to inflammation, hemostasis and thrombosis, immunity, hemodynamic mechanotransduction, and vascular repair [22]. For example, endothelial dysfunction promotes loss of thromboresistance and formation of mural thrombi, leading to vulnerable plaques causing ACS. Antithrombotic therapeutic strategies have been effectively utilized to treat ACS, including the use of ASA. Thrombolytic therapy has been effective in the early hours following an acute myocardial infarction to reestablish blood flow and reperfuse ischemic myocardial tissue.
4. Hemodynamic shear stress— injury, repair, and ACS Although the pathogenesis of atherosclerosis is a complex multifactorial process, blood flow-induced shear stress has emerged as an important factor in the pathogenesis of the focal fibroinflammatory lipid atherosclerotic plaque. Shear stress is a very small biomechanical force that is determined by blood flow, vessel geometry, and fluid viscosity and is computationally estimated using fluid dynamics models [23]. This parallel frictional drag force of shear stress is one of the most important blood flowinduced mechanical stresses acting to determine the structure and function of the vessel wall. The endothelium is exposed to different flow patterns; laminar flow, which is the steady tangential drag force noted above; oscillatory flow, where time averaged fluctuations in shear stress are very low or zero due to forward–reverse flow cycles; and disrupted flows, which exhibit regions of flow separation, recirculation, and reattachment that are associated with temporal and spatial shear gradients. The loss of laminar flow results in turbulent flow, which also has profound effects on the endothelium. Although shear stress causes very small bulk deformations of artery walls that are less than 1%, the vascular wall is continuously fine tuning its activities in response to shear stress because the endothelium is exquisitely sensitive to shear. Although hemodynamic shear stress was considered an important local risk factor in atherogenesis, it took studies over the past 20 years to define the role of shear stress and to begin to explore the molecular mechanisms by which hemodynamic physical forces control the regulation of numerous complex vascular biological process [22]. It has been shown that normal laminar flow induced shear stress is a critical factor in maintaining normal physiologic vascular function, including thromboresistance, barrier function and vascular homeostasis. However, shear stress, especially when blood flow is disrupted and/or is nonlaminar, plays a critical role in the pathogenesis of the
A.I. Gotlieb / Cardiovascular Pathology 14 (2005) 181–184
fibroinflammatory lipid atherosclerotic plaque, especially at sites where flow conditions are disturbed with low or oscillatory shear stress [24,25]. The altered arterial hemodynamics around curvatures, arterial branch ostia, and bifurcations, where secondary flows occur, enhances the atherogenic effects of the numerous systemic risk factors and genetic factors that have been identified to promote initiation and progression of the atherosclerotic lesion and, ultimately, the development of complicated plaques that lead to serious ACS [26]. It is likely that there are several possible mechanisms by which endothelial cells sense the physical force of shear stress and thus act as a shear transducer, including those mediated by gene expression and those not mediated by gene expression. Initial mechanosensing may occur at cell surfaces, resulting in immediate changes in cell function, as might occur, as cell membranes may be deformed, ions may be translocated across local membrane, and membrane associated biochemical responses may be activated. These events may alter cell function directly and/or may lead to the activation of downstream intracellular signaling pathways, which then may alter cell function and/or may activate specific endothelial genes to modulate endothelial function. Endothelial actin microfilaments, microtubules, integrin – matrix protein complexes, and cell–cell and cell substratum adhesion complexes are also thought to undergo both direct and indirect conformational changes, resulting in the mechanotransduction of shear stress. Endothelial dysfunction and disturbed hemodynamic shear stress lead to erosion and fissure formation on the surface of complicated fibroinflammatory lipid plaques [22]. These vulnerable plaques may become unstable, contributing to ACS and to plaque rupture [27,28]. Endothelial repair regulated, in part, by normal laminar flow induced hemodynamic shear stress may help to reestablish a stable surface in these unstable vulnerable plaques [22]. Rapid, efficient repair of the endothelium following focal endothelial wounding and denudation is regulated by a complex series of cellular processes [29 –32]. Directed cell migration, an early essential event in repair, is thought to be initiated by centrosome redistribution toward the front of the cell prior to the onset of migration [32]. As such, centrosomal polarity may be an important regulatory event in directed endothelial cell migration. Cdc42 acts as a molecular regulator of not only shear-induced MTOC polarization of Swiss 3T3 fibroblasts, but also shear-induced microtubule-dependent nucleus movement [33,34]. Basic fibroblast growth factor is a signal for the initiation of centrosome redistribution to the front of migrating endothelial cells at the edge of an in vitro wound [32]. Rho regulates centrosome redistribution and central microfilament remodeling during early endothelial wound repair, and bFGF promotes actin remodeling through a downstream Rho-dependent pathway and promotes centrosome redistribution, at least in part, with a Rho-independent pathway.
183
5. Endothelial stem/precursor cells The role of adult stem cells for the maintenance and regeneration of endothelium is a new area of vascular research that will have important impact on the diagnosis, treatment, and prevention of ACS. The concept is that endothelial precursor cells (EPCs) and/or adult stem cells, derived from the bone marrow, increase in number following vascular injury and physiological stress. They are then released into the peripheral circulation, somehow target injured vessel walls, attach to the denuded surface, and differentiate to reestablish endothelial integrity [35,36]. Numerous issues remain to be understood. Both the nature of the adult stem cells and EPC and how they differentiate need to be investigated. Although it is likely that specific cytokines and chemokines regulate some steps in mobilization of EPCs [35], the factors that trigger the activation and proliferation of these cells requires identification. The molecular mechanisms for regulation of cell function need to be understood, and the mechanisms of targeting injured vasculature, adhering to the sites and integrating into the mature endothelium, need to be investigated. Thus, the past 20 years have seen new technologies arise that have confirmed and advanced earlier hypotheses and theories on the pathogenesis of atherosclerosis, complicated and vulnerable plaques, and ACS. These technologies have provided new insights as well into the workings of the vessel wall in health and disease, especially at the cellular and molecular levels, and have led to new therapeutics, diagnostic, and preventative approaches to ACS. References [1] Gotlieb AI, Silver MD. Atherosclerosis: morphology and pathogenesis in cardiovascular pathology. In: Silver MD, Gotlieb AI, Schoen FJ, editors. Cardiovascular pathology. New York7 Churchill-Livingstone, 2001. pp. 68 – 106. [2] Fye WB. A historical perspective on atherosclerosis and coronary artery disease. In: Fuster V, Topol EJ, Nabel EG, editors. Atherothrombosis and coronary artery disease. 2nd ed. Philadelphia7 Lippincott Williams and Wilkins, 2005. pp. 1 – 14. [3] Virchow RCL. Cellular pathology: as based upon physiological and pathological histology. In: Chance F, editor. Translation. New York7 De Witt, 1858, pp. 338 – 66. [4] Rosenfeld ME, Polinsky P, Virmani R, Kauser K, Rubanyi G, Schwartz SM. Advanced atherosclerotic lesions in innominate artery of apoE knockout mice. Atheroscler Thromb Vasc Biol 2000;20:2587 – 92. [5] Miida T, Hirayama S, Nakamura Y. Cholesterol-independent effects of statins and new therapeutic targets: ischemic stroke and dementia. J Atheroscler Thromb 2004;11:253 – 64. [6] Conway EM. Angiogenesis: a link to thrombosis in athero-thrombotic disease. Pathophysiol Haemost Thromb 2003/2004;33:241 – 8. [7] Sobel BE, Taatjes DJ, Schneider DJ. Intramural plasminogen activator inhibitor Type-1 and coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2003;23:1979 – 89. [8] Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W, Rosenfeld M, Schwartz CJ, Wagner WD, Wissler RW. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Arterioscler Thromb Vasc Biol 1995; 15:1512 – 31.
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[9] Davies MJ, Thomas A. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N Engl J Med 1984;310:1137 – 40. [10] Davies MJ, Woolf N, Rowles PM, Pepper J. Morphology of the endothelium over atherosclerotic plaques in human coronary arteries. Br Heart J 1988;60:459 – 64. [11] van der Wai AC, Becker EC, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994;89:36 – 44. [12] Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med 1997;336:1276 – 82. [13] Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation 1994;90:775 – 8. [14] Kolodgie FD, Virmani R, Burke AP, et al. Pathologic assessment of the vulnerable human coronary plaque. Heart 2004;90:1385 – 91. [15] Ross R. The smooth muscle cell: II. Growth of smooth muscle in culture and formation of elastic fibers. J Cell Biol 1971;50:172. [16] Jaffe EA, Nachman RL, Becker CG, Minick CR. Culture of human endothelial cells derived from umbilical veins Identification by morphologic and immunologic criteria. J Clin Invest 1973;52:2745. [17] Gimbrone MA, Cotran RS, Folkman J. Human vascular endothelial cells in culture: growth and DNA synthesis. J Cell Biol 1974;60:673. [18] Booyse FM, Sedlak BJ, Rafelson ME. Culture of arterial endothelial cells: characterization and growth of bovine aortic cells. Thromb Diath Haemorrh 1975;34:825. [19] Andreotti F, Porto I, Crea F, Maseri A. Inflammatory gene polymorphism and ischemic heart disease: review of population association studies. Heart 2002;87:107 – 12. [20] Williams H, Johnson JJ, Carson KGS, Jackson CL. Characteristics of intact and ruptured atherosclerotic plaques in brachiocephalic arteries of apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol 2002;22:788 – 92. [21] Rosenfeld ME, Polinsky P, Virmani R, Kauser K, Rubanyi G, Schwartz SM. Advanced atherosclerotic lesions in the innominate artery of the ApoE knockout mouse. Arterioscler Thromb Vasc Biol 2000;20:2587 – 92. [22] Dickson BC, Gotlieb AI. Endothelial dysfunction and repair in the pathogenesis of stable and unstable fibroinflammatory atheromas. Can J Cardiol 2004;20(Suppl B);16B – 23B.
[23] Cunningham K, Gotlieb AI. The role of shear stress in atherogenesis. Lab Invest 2005;85:9 – 23. [24] Walpola PL, Gotlieb AI, Cybulsky MI, Langille BL. Expression of ICAM-1 and VCAM-1 and monocyte adherence in arteries exposed to altered shear-stress. Arterioscler Thromb Vasc Biol 1995; 15:2 – 10. [25] Vyalov S, Langille BL, Gotlieb AI. Decreased blood flow rate disrupts endothelial repair in vivo. Am J Pathol 1996;149:2107 – 18. [26] Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI. The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci U S A 2000;97:9052 – 7. [27] Aikawa M, Libby P. The vulnerable atherosclerotic plaque. Pathogenesis and therapeutic approach. Cardiovasc Pathol 2004;13:125 – 38. [28] Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest 1994;94: 2493 – 503. [29] Lee JSY, Gotlieb AI. Microtubule–actin interactions may regulate endothelial integrity and repair. Cardiovasc Pathol 2002;11:135 – 40. [30] Lee JSY, Gotlieb AI. Understanding the role of the cytoskeleton in the complex regulation of the endothelial repair. Histol Histopathol 2003;18:879 – 87. [31] Lee JSY, Gotlieb AI. Microtubules regulate aortic endothelial cell actin microfilament reorganization in intact and repairing monolayers. Histol Histopathol 2005;20:455 – 65. [32] Lee T-YJ, Gotlieb AI. Rho and bFGF involvement in centrosome redistribution and actin microfilament remodeling during early endothelial wound repair. J Vasc Surg 2002!1242 – 52. [33] Tzima E, Kiosses WB, del Pozzo MA, Schwartz MA. Localized Cdc 42 activation, detected using a novel assay, mediates microtubule organizing center positioning in endothelial cells in response to fluid shear stress. J Biol Chem 2003;278:31020 – 3. [34] Lee JSH, Tseng Y, Wirtz D. Cdc42 mediates nucleus movement and MTOC polarization in Swiss 3T3 fibroblasts under mechanical shear stress. Mol Biol Cell 2005!871 – 80. [35] Rafi S, Meeus S, Dias S, Hattori K, Heissig B, Shemelknov S, Rafii D, Lyden D. Contribution of marrow-derived progenitors to vascular cardiac regeneration. Cell Dev Biol 2002;13:61 – 7. [36] Murasawa S, Asahara T. Endothelial progenitor cells for vasculogenesis. Physiology 2005;10:36 – 42.
Review Article
Atherosclerosis and acute coronary syndromesB Avrum I. GotliebT Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada Department of Pathology, University Health Network, Toronto, Canada Received 23 March 2005; accepted 30 March 2005
Abstract In the past 20 years, there has been much new knowledge discovered on the pathogenesis of atherosclerosis and complicated and vulnerable plaques leading to a better understanding of acute coronary syndromes (ACS). The role of thrombosis, lipid metabolism, and inflammation has been investigated at the cellular and molecular levels, resulting in important new diagnostic and therapeutic strategies. The characterization of the role of hemodynamic shear stress and its regulation of cytoskeletal function in endothelial repair and the discovery of endothelial precursor cells (EPCs) derived from the bone marrow have provided new insight into vascular repair. Thus, our knowledge continues to increase, leading to improved prevention, diagnosis, and treatment of ACS. D 2005 Elsevier Inc. All rights reserved. Keywords: Atherosclerosis; Acute coronary syndromes; Endothelium; Cytoskeleton; Hemodynamic shear stress; Vascular repair
1. Introduction
2. Atherosclerosis
Coronary artery disease is the leading cause of mortality in the western world [1]. Acute coronary syndromes (ACS) are characterized clinically into three groups: patients with unstable angina, those with non-ST elevation myocardial infarction (non-STEMI), and those with ST elevation myocardial infarction (STEMI). The three clinical conditions have similar pathophysiologies, although each has different clinical features, therapies, and prognosis. The presence of atherothrombotic coronary artery occlusion due to plaque rupture and superimposed thrombosis with or without distal embolization is the common pathophysiology of ACS. The extent of lumen occlusion and the role of vasospasm is variable, thus, patients with unstable angina may have nonocclusive thrombi, leading to reduced myocardial perfusion.
The lesions of atherosclerosis were identified by anatomical pathologists well before establishing a causal association between the histopathology observations found in arteries at autopsy and the clinical syndromes of coronary artery disease. Atherosclerosis has been shown to be present as far back as ancient Egypt (reviewed in Ref. [2]). Jean Lobstein used the term arteriosclerosis in an 1829 pathology monograph. Carl Rokitansky promoted a thrombogenic theory of atherosclerosis in 1852. Rudolf Virchow, in 1858, identified the presence of intimal deposits in arteries. He focused his thinking on cells, connective tissue, and ultimately on vascular degeneration [3]. By the first decade of the 20th century, both Alexander Ignatovski and Nikolai Anitschkov carried out experiments that showed that egg yolk and pure cholesterol caused atherosclerosis in experimental animals. The hypercholesterolemic model of atherogenesis became a well-studied model, in many species, and has now been successfully extended to transgenic murine models, including mouse models with features of advanced human atherosclerotic plaques and elements of plaque instability [4]. The development of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins, to treat hypercholesterolemia has had a profound
B This article is based on a presentation at the Society for Cardiovascular Pathology Companion Meeting at the United States and Canadian Academy of Pathology, February 27, 2005, San Antonio, TX. T Department of Laboratory Medicine and Pathobiology, Banting Institute, University of Toronto, Room 110, 100 College Street, Toronto, Canada ON M5G 1L5. Tel.: +1 416 978 2557; fax: +1 416 978 7361. E-mail address: [email protected].
1054-8807/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.carpath.2005.03.007
182
A.I. Gotlieb / Cardiovascular Pathology 14 (2005) 181–184
therapeutic affect on ACS, and the recent identification of the nonlipid effects of statins that target a variety of biologic processes involved in atherogenesis and plaque vulnerability is an important advancement [5]. Alongside these lipid studies, the role of thrombosis in atherogenesis was being well studied, improving the understanding of platelet structure and function and of coagulation and fibrinolytic processes [6,7]. Elegant, detailed morphological and clinical pathologic studies in the past 20 –30 years by anatomic pathologists provided very important new knowledge that helped to focus and design studies on pathogenesis [8–14]. The field of atherogenesis began to utilize innovative biochemical, cellular, and molecular investigations on human biologic material, experimental animal models, and in in vitro systems to direct attention to cell function, especially that of monocyte/macrophages, endothelial, and smooth muscle cells. The technologies that were being utilized included genomics, proteomics, imaging (static and live cell imaging to understand molecular events), clinical chemistry, and interdisciplinary approaches involving integrative biology, bioengineering, computational biology, regenerative medicine, biomaterials, and clinical imaging. Today, the intense study of endothelial and smooth muscle cell function, hemodynamic shear stress, lipid deposition, macrophage function and inflammation, immune activity, neovascularization, thrombosis, matrix remodeling, and fibrous cap rupture [1] has been made possible by the major advance of being able to culture pure vascular endothelial cells and smooth muscle cells, which was established in the late 1970s and early 1980s [15–18]. Investigations on the pathogenesis of atherosclerosis also led to a better understanding of the clinical conditions of ACS [9–14], especially in relation to the structure and function of the fibroinflammatory lipid plaque and its complications. Studies were now directed at the pathogenesis, diagnosis, risk stratification, and treatment using well-conceived clinical practice guidelines of ACS, especially as they relate to thrombosis, plaque rupture, and plaque growth. In addition, the contribution of genetic risk factors to the development of ACS is being very actively studied. Proinflammatory gene polymorphisms have now become an important area of study to understand the development of atheromatous plaque vulnerability [19]. Two major outstanding questions will benefit from ongoing state-of-the-art research studies. The questions are why the thrombotic response in the lumen is not necessarily associated with the extent of the rupture in individual patients and why is it that angiographically identified minor to moderate plaques do rupture. Answers to these issues will identify important biologic processes that may be targeted to prevent and/or treat ACS. Novel transgenic mouse models, recently identified and characterized, that have complicated atherosclerotic plaques with characteristics similar to human vulnerable plaques are likely to become an important model to study plaque rupture [20,21].
3. The endothelium, integrator of normal and abnormal vascular biology The endothelium functions as a permeability barrier, a thromboresistant surface, and as an initiator and/or inhibitor of numerous biologic processes, especially those related to inflammation, hemostasis and thrombosis, immunity, hemodynamic mechanotransduction, and vascular repair [22]. For example, endothelial dysfunction promotes loss of thromboresistance and formation of mural thrombi, leading to vulnerable plaques causing ACS. Antithrombotic therapeutic strategies have been effectively utilized to treat ACS, including the use of ASA. Thrombolytic therapy has been effective in the early hours following an acute myocardial infarction to reestablish blood flow and reperfuse ischemic myocardial tissue.
4. Hemodynamic shear stress— injury, repair, and ACS Although the pathogenesis of atherosclerosis is a complex multifactorial process, blood flow-induced shear stress has emerged as an important factor in the pathogenesis of the focal fibroinflammatory lipid atherosclerotic plaque. Shear stress is a very small biomechanical force that is determined by blood flow, vessel geometry, and fluid viscosity and is computationally estimated using fluid dynamics models [23]. This parallel frictional drag force of shear stress is one of the most important blood flowinduced mechanical stresses acting to determine the structure and function of the vessel wall. The endothelium is exposed to different flow patterns; laminar flow, which is the steady tangential drag force noted above; oscillatory flow, where time averaged fluctuations in shear stress are very low or zero due to forward–reverse flow cycles; and disrupted flows, which exhibit regions of flow separation, recirculation, and reattachment that are associated with temporal and spatial shear gradients. The loss of laminar flow results in turbulent flow, which also has profound effects on the endothelium. Although shear stress causes very small bulk deformations of artery walls that are less than 1%, the vascular wall is continuously fine tuning its activities in response to shear stress because the endothelium is exquisitely sensitive to shear. Although hemodynamic shear stress was considered an important local risk factor in atherogenesis, it took studies over the past 20 years to define the role of shear stress and to begin to explore the molecular mechanisms by which hemodynamic physical forces control the regulation of numerous complex vascular biological process [22]. It has been shown that normal laminar flow induced shear stress is a critical factor in maintaining normal physiologic vascular function, including thromboresistance, barrier function and vascular homeostasis. However, shear stress, especially when blood flow is disrupted and/or is nonlaminar, plays a critical role in the pathogenesis of the
A.I. Gotlieb / Cardiovascular Pathology 14 (2005) 181–184
fibroinflammatory lipid atherosclerotic plaque, especially at sites where flow conditions are disturbed with low or oscillatory shear stress [24,25]. The altered arterial hemodynamics around curvatures, arterial branch ostia, and bifurcations, where secondary flows occur, enhances the atherogenic effects of the numerous systemic risk factors and genetic factors that have been identified to promote initiation and progression of the atherosclerotic lesion and, ultimately, the development of complicated plaques that lead to serious ACS [26]. It is likely that there are several possible mechanisms by which endothelial cells sense the physical force of shear stress and thus act as a shear transducer, including those mediated by gene expression and those not mediated by gene expression. Initial mechanosensing may occur at cell surfaces, resulting in immediate changes in cell function, as might occur, as cell membranes may be deformed, ions may be translocated across local membrane, and membrane associated biochemical responses may be activated. These events may alter cell function directly and/or may lead to the activation of downstream intracellular signaling pathways, which then may alter cell function and/or may activate specific endothelial genes to modulate endothelial function. Endothelial actin microfilaments, microtubules, integrin – matrix protein complexes, and cell–cell and cell substratum adhesion complexes are also thought to undergo both direct and indirect conformational changes, resulting in the mechanotransduction of shear stress. Endothelial dysfunction and disturbed hemodynamic shear stress lead to erosion and fissure formation on the surface of complicated fibroinflammatory lipid plaques [22]. These vulnerable plaques may become unstable, contributing to ACS and to plaque rupture [27,28]. Endothelial repair regulated, in part, by normal laminar flow induced hemodynamic shear stress may help to reestablish a stable surface in these unstable vulnerable plaques [22]. Rapid, efficient repair of the endothelium following focal endothelial wounding and denudation is regulated by a complex series of cellular processes [29 –32]. Directed cell migration, an early essential event in repair, is thought to be initiated by centrosome redistribution toward the front of the cell prior to the onset of migration [32]. As such, centrosomal polarity may be an important regulatory event in directed endothelial cell migration. Cdc42 acts as a molecular regulator of not only shear-induced MTOC polarization of Swiss 3T3 fibroblasts, but also shear-induced microtubule-dependent nucleus movement [33,34]. Basic fibroblast growth factor is a signal for the initiation of centrosome redistribution to the front of migrating endothelial cells at the edge of an in vitro wound [32]. Rho regulates centrosome redistribution and central microfilament remodeling during early endothelial wound repair, and bFGF promotes actin remodeling through a downstream Rho-dependent pathway and promotes centrosome redistribution, at least in part, with a Rho-independent pathway.
183
5. Endothelial stem/precursor cells The role of adult stem cells for the maintenance and regeneration of endothelium is a new area of vascular research that will have important impact on the diagnosis, treatment, and prevention of ACS. The concept is that endothelial precursor cells (EPCs) and/or adult stem cells, derived from the bone marrow, increase in number following vascular injury and physiological stress. They are then released into the peripheral circulation, somehow target injured vessel walls, attach to the denuded surface, and differentiate to reestablish endothelial integrity [35,36]. Numerous issues remain to be understood. Both the nature of the adult stem cells and EPC and how they differentiate need to be investigated. Although it is likely that specific cytokines and chemokines regulate some steps in mobilization of EPCs [35], the factors that trigger the activation and proliferation of these cells requires identification. The molecular mechanisms for regulation of cell function need to be understood, and the mechanisms of targeting injured vasculature, adhering to the sites and integrating into the mature endothelium, need to be investigated. Thus, the past 20 years have seen new technologies arise that have confirmed and advanced earlier hypotheses and theories on the pathogenesis of atherosclerosis, complicated and vulnerable plaques, and ACS. These technologies have provided new insights as well into the workings of the vessel wall in health and disease, especially at the cellular and molecular levels, and have led to new therapeutics, diagnostic, and preventative approaches to ACS. References [1] Gotlieb AI, Silver MD. Atherosclerosis: morphology and pathogenesis in cardiovascular pathology. In: Silver MD, Gotlieb AI, Schoen FJ, editors. Cardiovascular pathology. New York7 Churchill-Livingstone, 2001. pp. 68 – 106. [2] Fye WB. A historical perspective on atherosclerosis and coronary artery disease. In: Fuster V, Topol EJ, Nabel EG, editors. Atherothrombosis and coronary artery disease. 2nd ed. Philadelphia7 Lippincott Williams and Wilkins, 2005. pp. 1 – 14. [3] Virchow RCL. Cellular pathology: as based upon physiological and pathological histology. In: Chance F, editor. Translation. New York7 De Witt, 1858, pp. 338 – 66. [4] Rosenfeld ME, Polinsky P, Virmani R, Kauser K, Rubanyi G, Schwartz SM. Advanced atherosclerotic lesions in innominate artery of apoE knockout mice. Atheroscler Thromb Vasc Biol 2000;20:2587 – 92. [5] Miida T, Hirayama S, Nakamura Y. Cholesterol-independent effects of statins and new therapeutic targets: ischemic stroke and dementia. J Atheroscler Thromb 2004;11:253 – 64. [6] Conway EM. Angiogenesis: a link to thrombosis in athero-thrombotic disease. Pathophysiol Haemost Thromb 2003/2004;33:241 – 8. [7] Sobel BE, Taatjes DJ, Schneider DJ. Intramural plasminogen activator inhibitor Type-1 and coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2003;23:1979 – 89. [8] Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W, Rosenfeld M, Schwartz CJ, Wagner WD, Wissler RW. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Arterioscler Thromb Vasc Biol 1995; 15:1512 – 31.
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