Triggering Myocardial Infarction
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《新英格兰医药杂志》
Enormous progress made during the past few decades has dramatically enhanced our understanding of the pathobiology and pathophysiology responsible for acute myocardial infarction. Investigations in vascular biology have elucidated the critical role of growth factors, the proliferation of smooth-muscle cells, and the central role of inflammation in the initiation and progression of atherosclerosis.1 Research has also focused on the initiating events or "triggers" that qualitatively alter the stable or quiescent phase of coronary atherosclerosis and initiate a cascade of events that culminates in acute myocardial infarction. Some triggering phenomena may exert a single, transient effect on the pathophysiologic process, such as a surge of sympathetic activity, whereas others exert a more varied and pervasive effect, amplifying risk at multiple points and over a longer period. In this issue of the Journal, Peters et al. (pages 1721–1730) provide compelling epidemiologic evidence that particulate air pollution from traffic may trigger the abrupt onset of acute myocardial infarction. An understanding of air pollution in the larger context of triggering of the entire process of atherosclerosis suggests, in addition, that air pollution plays a more complex and multifaceted role in the development of cardiovascular disease over the longer term.
As initially described 15 years ago, the triggering of acute myocardial infarction typically begins with the so-called vulnerable or high-risk coronary atherosclerotic plaque, a focal lesion in jeopardy of plaque disruption.2 The vulnerable plaque is usually an inflamed, thin-cap fibroatheroma, characterized by a lipid-rich, atheromatous core with cholesterol crystals and necrotic debris, a thin fibrous cap with an infiltration of macrophages and lymphocytes, and decreased smooth-muscle-cell content, and associated with expansive remodeling of the outer vessel wall.3 The inflammatory cells associated with this type of high-risk plaque express a variety of cytokines and chemokines that contribute to inflammation and oxidative stress, as well as matrix metalloproteinases that can degrade the extracellular matrix, thereby weakening the plaque's fibrous cap and rendering it prone to rupture. Other, less common, coronary plaques that are prone to disruption may be characterized by extensive proliferation of smooth-muscle cells in a proteoglycan-rich matrix without the accompanying intense inflammation and thin fibrous cap; in such cases, a thrombus may form from a superficial erosion of the endothelial surface.
In persons with such a pathobiologic substrate of vulnerable plaque, the initiating event or trigger that may lead to the disruption of the plaque is often an external activity associated with increased sympathetic stimulation, such as physical or emotional stress or vasoconstriction. This trigger may lead very rapidly to the rupture of the vulnerable plaque, exposing the bloodstream to the thrombogenic contents of the plaque or the denuded endothelial surface, leading to rapid thrombus formation and, consequently, acute myocardial infarction. An additional trigger or initiating process, such as a transient increase in coagulability, inflammation, viscosity, or vasoconstriction, may further predispose to the formation of a thrombus.
Recently, it has been suggested that the sites at which triggers contribute to the development of acute myocardial infarction can be extended proximally in the pathophysiologic process4 (see Figure). Although atherosclerosis may affect the coronary tree diffusely, the principal manifestations of coronary plaque are highly focal. In a susceptible person with an adverse risk-factor profile, local hemodynamic disturbances, such as small areas of disturbed coronary blood flow and low shear stress, constitute the initiating event or trigger leading to focal atherosclerotic plaque formation and progression, which may continue for years. Although there may be many such areas of intimal thickening in early stages of atherosclerosis, only a subgroup, and perhaps a very small subgroup, of these coronary plaques become inflamed or vulnerable at any one time. Other plaques may acquire characteristics of fibrosis and scarring, and still others may remain quiescent.
Figure. Cascade of Triggers Culminating in Acute Myocardial Infarction.
There are multiple stages in the atherosclerotic process culminating in thrombosis and acute myocardial infarction: initial formation of plaque in a focal area of the artery; progression of some plaques to become vulnerable to disruption; precipitation of plaque disruption through either rupture or erosion; and transient exacerbation of a prothrombotic environment. Identifiable factors or determinants, referred to as triggers, are responsible for the development of each of these stages. These factors may be transient, such as an abrupt event that rapidly leads to plaque disruption or a brief exacerbation of prothrombotic conditions, or they may be longer-term determinants, such as systemic inflammation, a local vascular response to plaque formation leading to focal plaque inflammation, or a local area of flow disturbance leading to the initiation of atherosclerosis. CAD denotes coronary artery disease.
The triggering factors that determine which of those early plaques will progress and become inflamed are unknown, but it is likely that local hemodynamic factors, local vascular-remodeling responses, and the degree of systemic inflammation all contribute. Plaques that are inflamed and prone to rupture are those in which there is expansive or outward remodeling of the arterial wall, whereas those that are more fibrotic and scarred, without active inflammation, are associated with constrictive or inward remodeling. The divergent vascular-remodeling characteristics most likely reflect the balance in the dynamic regulation of collagen synthesis and breakdown.
Epidemiologic studies have long demonstrated the increased cardiac morbidity and mortality associated with particulate air pollution, and recent investigations have focused on the mechanistic role of air pollution in cardiovascular disease.5 Inhalation of particulate air pollution into the lungs leads to both pulmonary and systemic inflammation, with induction of cytokines and chemokines and generation of oxidative species. These injurious molecules create and exacerbate inflammation and oxidative stress, which lead to direct vascular injury, atherosclerosis, and autonomic dysfunction. Particulate air pollution also rapidly leads to a significant increase in fibrinogen, plasma viscosity, and platelet activation, as well as the release of endothelins, a family of potent vasoconstrictor molecules. Studies in animals have clearly documented the short- and long-term adverse effects of particulate air pollution on each step of the triggering cascade of coronary disease culminating in acute myocardial infarction: accelerated atherosclerosis, vasoconstriction, and increased thrombogenesis.
The association between exposure to traffic and the abrupt onset of myocardial infarction described by Peters et al. suggests that particulate air pollution from traffic may have led to abrupt plaque disruption and perhaps to the exacerbation of a thrombogenic environment. Transient, intense inflammation, vasoconstriction, and increased coagulability, alone or in combination, are potential culprits in this process.
In addition to these extremely short-term effects of particulate air pollution, its deleterious longer-term effects on the entire gamut of atherosclerotic triggers cannot be overemphasized. Decades of epidemiologic evidence underscore the cardiovascular morbidity and mortality related to air pollution. The proinflammatory, proatherosclerotic, and prothrombotic effects of particulate air pollution are compelling. As both epidemiologic and now mechanistic evidence mounts, there is greater urgency to accelerate our efforts to reduce particulate air pollution and to improve cardiovascular health.
Dr. Stone reports having received grant support from Boston Scientific and Pfizer.
Source Information
From the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston.
References
Libby P. Inflammation in atherosclerosis. Nature 2002;420:868-874.
Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 1989;79:733-743.
Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1262-1275.
Stone PH, Coskun AU, Yeghiazarians Y, et al. Prediction of sites of coronary atherosclerosis progression: in vivo profiling of endothelial shear stress, lumen, and outer vessel wall characteristics to predict vascular behavior. Curr Opin Cardiol 2003;18:458-470.
Brook RD, Franklin B, Cascio W, et al. Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association. Circulation 2004;109:2655-2671.
Related Letters:
Traffic and Myocardial Infarction
Tosteson D. C., Greenbaum D. S., Lebwohl B., Stone P. H.(Peter H. Stone, M.D.)
As initially described 15 years ago, the triggering of acute myocardial infarction typically begins with the so-called vulnerable or high-risk coronary atherosclerotic plaque, a focal lesion in jeopardy of plaque disruption.2 The vulnerable plaque is usually an inflamed, thin-cap fibroatheroma, characterized by a lipid-rich, atheromatous core with cholesterol crystals and necrotic debris, a thin fibrous cap with an infiltration of macrophages and lymphocytes, and decreased smooth-muscle-cell content, and associated with expansive remodeling of the outer vessel wall.3 The inflammatory cells associated with this type of high-risk plaque express a variety of cytokines and chemokines that contribute to inflammation and oxidative stress, as well as matrix metalloproteinases that can degrade the extracellular matrix, thereby weakening the plaque's fibrous cap and rendering it prone to rupture. Other, less common, coronary plaques that are prone to disruption may be characterized by extensive proliferation of smooth-muscle cells in a proteoglycan-rich matrix without the accompanying intense inflammation and thin fibrous cap; in such cases, a thrombus may form from a superficial erosion of the endothelial surface.
In persons with such a pathobiologic substrate of vulnerable plaque, the initiating event or trigger that may lead to the disruption of the plaque is often an external activity associated with increased sympathetic stimulation, such as physical or emotional stress or vasoconstriction. This trigger may lead very rapidly to the rupture of the vulnerable plaque, exposing the bloodstream to the thrombogenic contents of the plaque or the denuded endothelial surface, leading to rapid thrombus formation and, consequently, acute myocardial infarction. An additional trigger or initiating process, such as a transient increase in coagulability, inflammation, viscosity, or vasoconstriction, may further predispose to the formation of a thrombus.
Recently, it has been suggested that the sites at which triggers contribute to the development of acute myocardial infarction can be extended proximally in the pathophysiologic process4 (see Figure). Although atherosclerosis may affect the coronary tree diffusely, the principal manifestations of coronary plaque are highly focal. In a susceptible person with an adverse risk-factor profile, local hemodynamic disturbances, such as small areas of disturbed coronary blood flow and low shear stress, constitute the initiating event or trigger leading to focal atherosclerotic plaque formation and progression, which may continue for years. Although there may be many such areas of intimal thickening in early stages of atherosclerosis, only a subgroup, and perhaps a very small subgroup, of these coronary plaques become inflamed or vulnerable at any one time. Other plaques may acquire characteristics of fibrosis and scarring, and still others may remain quiescent.
Figure. Cascade of Triggers Culminating in Acute Myocardial Infarction.
There are multiple stages in the atherosclerotic process culminating in thrombosis and acute myocardial infarction: initial formation of plaque in a focal area of the artery; progression of some plaques to become vulnerable to disruption; precipitation of plaque disruption through either rupture or erosion; and transient exacerbation of a prothrombotic environment. Identifiable factors or determinants, referred to as triggers, are responsible for the development of each of these stages. These factors may be transient, such as an abrupt event that rapidly leads to plaque disruption or a brief exacerbation of prothrombotic conditions, or they may be longer-term determinants, such as systemic inflammation, a local vascular response to plaque formation leading to focal plaque inflammation, or a local area of flow disturbance leading to the initiation of atherosclerosis. CAD denotes coronary artery disease.
The triggering factors that determine which of those early plaques will progress and become inflamed are unknown, but it is likely that local hemodynamic factors, local vascular-remodeling responses, and the degree of systemic inflammation all contribute. Plaques that are inflamed and prone to rupture are those in which there is expansive or outward remodeling of the arterial wall, whereas those that are more fibrotic and scarred, without active inflammation, are associated with constrictive or inward remodeling. The divergent vascular-remodeling characteristics most likely reflect the balance in the dynamic regulation of collagen synthesis and breakdown.
Epidemiologic studies have long demonstrated the increased cardiac morbidity and mortality associated with particulate air pollution, and recent investigations have focused on the mechanistic role of air pollution in cardiovascular disease.5 Inhalation of particulate air pollution into the lungs leads to both pulmonary and systemic inflammation, with induction of cytokines and chemokines and generation of oxidative species. These injurious molecules create and exacerbate inflammation and oxidative stress, which lead to direct vascular injury, atherosclerosis, and autonomic dysfunction. Particulate air pollution also rapidly leads to a significant increase in fibrinogen, plasma viscosity, and platelet activation, as well as the release of endothelins, a family of potent vasoconstrictor molecules. Studies in animals have clearly documented the short- and long-term adverse effects of particulate air pollution on each step of the triggering cascade of coronary disease culminating in acute myocardial infarction: accelerated atherosclerosis, vasoconstriction, and increased thrombogenesis.
The association between exposure to traffic and the abrupt onset of myocardial infarction described by Peters et al. suggests that particulate air pollution from traffic may have led to abrupt plaque disruption and perhaps to the exacerbation of a thrombogenic environment. Transient, intense inflammation, vasoconstriction, and increased coagulability, alone or in combination, are potential culprits in this process.
In addition to these extremely short-term effects of particulate air pollution, its deleterious longer-term effects on the entire gamut of atherosclerotic triggers cannot be overemphasized. Decades of epidemiologic evidence underscore the cardiovascular morbidity and mortality related to air pollution. The proinflammatory, proatherosclerotic, and prothrombotic effects of particulate air pollution are compelling. As both epidemiologic and now mechanistic evidence mounts, there is greater urgency to accelerate our efforts to reduce particulate air pollution and to improve cardiovascular health.
Dr. Stone reports having received grant support from Boston Scientific and Pfizer.
Source Information
From the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston.
References
Libby P. Inflammation in atherosclerosis. Nature 2002;420:868-874.
Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation 1989;79:733-743.
Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000;20:1262-1275.
Stone PH, Coskun AU, Yeghiazarians Y, et al. Prediction of sites of coronary atherosclerosis progression: in vivo profiling of endothelial shear stress, lumen, and outer vessel wall characteristics to predict vascular behavior. Curr Opin Cardiol 2003;18:458-470.
Brook RD, Franklin B, Cascio W, et al. Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association. Circulation 2004;109:2655-2671.
Related Letters:
Traffic and Myocardial Infarction
Tosteson D. C., Greenbaum D. S., Lebwohl B., Stone P. H.(Peter H. Stone, M.D.)