Knowledge about the biology of human atherosclerosis and the risk factors for the disease has expanded considerably. The application of vascular biology to human atherosclerosis has revealed many new insights into the mechanisms that promote clinical events. The series of figures and animated video presentations presented here illustrates some of the evolving information about risk factors for atherosclerosis and the pathophysiology of clinical events.
The importance of blood pressure as a risk factor for atherosclerosis and cardiovascular events has long been recognized. More recent clinical information has highlighted the importance of pulse pressure—the difference between the systolic pressure and minimum diastolic arterial pressure—as a prognostic indicator of cardiovascular risk. The video clip on pulse pressure explains the pathophysiology of this readily measured clinical variable.
Physicians possess a great deal of knowledge about the role of cholesterol in the prediction of atherosclerosis and its complications, but knowledge about the mechanism that links hypercholesterolemia to cardiovascular events has lagged the epidemiologic and observational findings. Low-density lipoprotein (LDL) provides an example of a well-understood causal cardiovascular risk factor. Several of the animations included in this series highlight the role of modified LDL as a trigger for inflammation and other aspects of the pathobiology of arterial plaques that lead to their aggravation and clinical events. Physicians have useful tools for modulating LDL, but other aspects of dyslipidemia are on the rise and provide a growing challenge to the practitioner. In particular, low levels of high-density lipoprotein (HDL) and elevated levels of triglycerides characterize the constellation of findings denoted by some as “metabolic syndrome.” In the wake of increasing obesity and diabetes mellitus worldwide, these features of the lipoprotein profile require renewed focus. Several of the animations in this collection discuss the concept of metabolic syndrome and the role of lipid profile components other than LDL in atherogenesis.
The traditional approach to atherosclerosis focused on arterial stenoses as a cause of ischemia and cardiovascular events. Physicians now have effective revascularization modalities for addressing flow-limiting stenoses, but atherosclerotic plaques that do not cause stenoses nonetheless may precipitate clinical events, such as unstable angina and acute myocardial infarction. Thus, it is necessary to add to the traditional focus on stenosis an enlarged appreciation of the pathobiology of atherosclerosis that underlies many acute coronary syndromes. The animation on the development and complication of atherosclerotic plaque explains some of these emerging concepts in plaque activation as they apply to the precipitation of thrombotic complications of atherosclerosis.
Atherosclerosis affects multiple arterial beds. Atherosclerosis has different manifestations depending on the arterial bed affected, as depicted in this figure. Although risk factors for atherosclerosis such as hypertension, smoking, and hypercholesterolemia are systemic, atherosclerosis tends to affect particular regions of the arterial tree selectively. Regions of disturbed flow or interruption of usual laminar shear stress due to branching points show particular susceptibility to atheroma formation. (Reprinted by permission from Springer Nature: Springer, Nature Reviews Disease Primers 5:56, Atherosclerosis, P Libby et al, 2019.)
Views of the pathogenesis of atherosclerosis have changed through the years. In the mid-nineteenth century the German pathologists Virchow and von Rokitansky promulgated competing theories of atherogenesis. Virchow viewed atherosclerosis as including an inflammatory component (upper left), whereas von Rokitansky argued for incorporation of mural thrombus as a key to atheroma formation (upper right). The observation that a diet enriched in cholesterol could give rise to experimental fatty plaques led to the ascendancy of the cholesterol hypothesis of atherosclerosis (middle right). The chemical characterization of the lipoproteins and the elucidation of the low-density lipoprotein receptor pathway in conjunction with convincing observational epidemiologic as well as human genetic evidence established low-density lipoprotein as an indubitably causal risk factor for atherosclerosis. The introduction and success in reducing atherosclerotic events of the statin class of drugs reinforced the role of cholesterol and low-density lipoprotein in atherogenesis. The advent of contemporary cell biology and the ability to culture smooth muscle and endothelial cells led to a focus on smooth muscle cell proliferation and elaboration of extracellular matrix components (bottom center). Initial formulations of this “response to injury” hypothesis did not incorporate inflammatory cells or their products in the pathogenesis of atherosclerosis. Later work identified the participation of both innate and adaptive immunity as important modulators of atherosclerosis (middle left). Our contemporary view of atherogenesis incorporates elements all of these seemingly competing theories (center). (Reproduced with permission from P Libby, GK Hansson: From focal lipid storage to systemic inflammation. J Am Coll Cardiol 74:1594, 2019.)
Modifiers of atherosclerosis and the inflammatory response. A variety of traditional and less well-established risk factors can contribute to atherosclerotic risk (top). Traditional risk factors include smoking, lipid abnormalities, hypertension, and diabetes/glucose intolerance. Emerging risk factors include ectopic adipose tissue, local sites of inflammation such as periodontal or rheumatologic diseases, and the microbiome. Many of these risk factors can elicit the overexpression of proinflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor α (TNF-α), CD40 ligand (CD154), or monocyte chemoattractant protein-1 (MCP-1, CCL2). A number of lifestyle or behavioral habits may mitigate cardiovascular risk including physical activity, a diet that avoids obesity, consumption of omega-3 fatty acids derived from fish, and moderate alcohol. The balance between pro- and anti-inflammatory or pro-resolving signals can lead to activation of the acute-phase response in the hepatocyte. The acute-phase reactants include fibrinogen, the precursor of clots, and plasminogen activator inhibitor-1 (PAI-1), a blocker of endogenous fibrinolysis. These proteins, when produced excessively, can promote thrombus accumulation. C-reactive protein (CRP) and serum amyloid A (SAA) report on the acute-phase response and have become biomarkers of inflammation, particularly CRP measured with a highly sensitive assay (hsCRP). (Reproduced with permission from P Libby, F Crea: Clinical implications of inflammation for cardiovascular primary prevention. Eur Heart J 31:777, 2010.)
Inflammation in early atherogenesis. Risk factors shown in Fig. A10-3 can activate an inflammatory response that involves arms of the innate immune system, exemplified by the monocytes depicted, and the adaptive immune system, exemplified by the T lymphocytes portrayed here. Adhesion molecules expressed by activated endothelial cells that have encountered inflammatory mediators recruit these immune cells to the artery wall. Chemokines produced by intimal cells can direct the migration of the attached inflammatory cells. The atherosclerotic plaque forms in the innermost layer of the artery, the intima, which overlies the middle layer, the media, populated primarily by resting smooth muscle cells embedded in extracellular matrix. Monocytes can mature into macrophages and accumulate lipid derived from lipoprotein particles such as low-density lipoprotein (LDL) that accumulate in the artery wall. This lipid overload gives rise to foam cells, a hallmark of the atherosclerotic lesion. The immune cells can produce mediators that cause the migration and proliferation of smooth muscle cells, usually resident primarily in the tunica media below the intimal layer. The smooth muscle cells can synthesize a rich extracellular matrix that can entrap further lipoproteins and contribute to the bulk of the evolving atherosclerotic plaque. Some inflammatory cells can also accumulate in the outermost layer of the artery, the adventitia, as exemplified by the mast cell in this diagram. (Reprinted by permission from Springer Nature: Springer, Nature Reviews Disease Primers 5:56. Atherosclerosis, P Libby et al, 2019.)
The established atherosclerotic plaque evolves by cellular birth and death. The smooth muscle cells (SMCs) that have accumulated in the intimal lesion can die and release mediators or elaborate microparticles that bear messengers that can contribute to propagation and maintenance of a local inflammatory state. The mononuclear phagocytes, including foam cells, can also perish and contribute to the bulk of the central necrotic core of the typical atherosclerotic plaque. Macrophages can replicate within the artery wall. Impaired clearance of dead cells, known as efferocytosis, can contribute to the formation of the lipid core. Current evidence supports the metaplasia of some smooth muscle cells into cells that resemble morphologically and bear markers of macrophages. The mononuclear phagocytes stimulated by inflammatory mediators produce proteinases specialized in breaking down the plaque extracellular matrix, including the triple helical interstitial collagen molecules that lend strength to the plaque’s fibrous cap that overlies the necrotic core. The degradation of the interstitial collagen can facilitate the fissure, fracture, or frank rupture of plaques that permits contact with the coagulation factors in blood with thrombogenic material in the plaque’s lipid core, for example, tissue factor procoagulant. These physical disruptions of the mature atherosclerotic plaque can trigger local thrombosis. LDL, low-density lipoprotein. (Reprinted by permission from Springer Nature: Springer, Nature Reviews Disease Primers 5:56. Atherosclerosis, P Libby et al, 2019.)
Distinctions between two different mechanisms of plaque disruption: fissure of the fibrous cap versus superficial erosion. In addition to fracture of the plaque’s fibrous cap shown on the right side of this diagram, superficial erosion of the endothelial lining of the intimal lesion can also provoke thrombosis. Superficial erosion causes a quarter to a third of acute coronary syndromes in the current era. The boxes depict the contrasting features of these two forms of plaque disruption that can give rise to thrombi. NETs, neutrophil extracellular traps; NSTEMI, non-ST-segment elevation myocardial infarction; PMN, polymorphonuclear leukocytes; STEMI, ST-segment elevation myocardial infarction. (Reproduced with permission from P Libby: Superficial erosion and the precision management of acute coronary syndromes: not one-size-fits-all. Eur Heart J 38:801, 2017.)
Lipid lowering renders atherosclerotic plaques less prone to provoke thrombotic complications. A combination of experimental and human imaging studies has shown that lipid lowering, for example, by intensive statin treatment, has little effect on the lumen caliber but can consistently shrink the lipid core, increase the relative content of fibrous tissue, and seemingly paradoxically increase the amount of calcified tissue. These morphologic changes in plaque character help to understand how lipid lowering prevents cardiovascular events. For example, the relative increase in extracellular matrix can render the plaque less likely to undergo disruption, thus limiting this trigger thrombosis. (Reproduced with permission from P Libby: How does lipid lowering prevent coronary events? New insights from human imaging trials. Eur Heart J 36:472, 2015.)
Thrombotic complications of atheroma depend on both the solid state of the plaque and the fluid phase of blood. The thrombotic potential of a plaque depends on procoagulants such as tissue factor produced by plaque macrophages. Also, the endothelial surface can undergo a shift in the balance of prothrombotic and antifibrinolytic properties that can potentiate clot formation and limit local fibrinolysis. In addition to the “solid state” of the plaque itself, the blood composition (the “fluid phase”) can determine the fate of a nascent thrombus. For example, high circulating levels of fibrinogen or plasminogen activator inhibitor (PAI-1) can favor thrombus accumulation, and circulating tissue factor microparticles may also trigger thrombosis. (Reproduced with permission from P Libby, P Theroux: Pathophysiology of coronary artery disease. Circulation 111:3481, 2005.)
Thrombosis intertwines intricately with inflammation. The thrombin molecule can activate not only the platelet but also the intrinsic cells of the vessel wall and endothelial and smooth muscle cells. The activated platelet can release a series of proinflammatory mediators, as can the endothelial and smooth muscle cells that have encountered thrombin or other proinflammatory stimuli. These cells can all release proinflammatory mediators such CD40 ligand (CD154), RANTES, or interleukin 6 (IL-6), a cytokine that stimulates the hepatic acute-phase response, which is implicated by strong human genetic evidence as causal in provoking atherosclerotic events. These proinflammatory mediators impinge on the mononuclear phagocyte eliciting amplifiers of thrombosis, inflammation, and oxidative stress. (Reproduced with permission from K Croce, P Libby: Intertwining of thrombosis and inflammation in atherosclerosis. Curr Opin Hematol 14:55, 2007.)
The continuum of atherosclerotic cardiovascular disease. The cardiovascular continuum depicted here shows that plaque thrombosis can beget acute myocardial infarction, an inflammatory state that can boost leukocyte production in the bone marrow, both by release of proinflammatory mediators such interleukin 1 beta (IL-1β) and by a stress response mediated by the sympathetic nervous system and beta 3 (β3) adrenergic agonism. Leukocytes derived from the bone marrow or stored in the spleen can home to the coronary artery, perpetuating a vicious cycle whereby inflammation begets thrombotic complications of atherosclerosis, which in turn perpetuate these processes. (Reproduced with permission from P Libby, GK Hansson: From focal lipid storage to systemic inflammation. J Am Coll Cardiol 74:1594, 2019.)
Remote inflammatory conditions can potentiate atherothrombosis. The associations between various rheumatologic conditions depicted in this diagram and increased atherosclerotic plaque burden and more frequent thrombotic complications underscore this relationship. Figure A10-10 depicts the mechanisms whereby local inflammation at remote sites can incite or augment inflammation within the atheroma itself. (From JC Mason, P Libby: Cardiovascular disease in patients with chronic inflammation: Mechanisms underlying premature cardiovascular events in rheumatologic conditions. Eur Heart J 36:482, 2015, Figure 1.)
Relationships between cancer and atherosclerosis. Atherosclerosis and cancer share many common mechanisms. At the outset, cancer most often arises from a gene mutation, while atherosclerosis usually associates with excessive risk factors such as those depicted in Figure A10-3. Yet, the ensuing biological events share many processes and mediators as depicted in this diagram. This concept illustrates that pathologic processes in tissues generally reflect a limited number of responses that share mechanisms between various conditions encountered by internal medicine physicians. DM, diabetes mellitus; HBP, high blood pressure; LDL, low-density lipoprotein. (Reproduced with permission from P Libby, S Kobold: Inflammation: A common contributor to cancer, aging, and cardiovascular diseases - expanding the concept of cardio-oncology. Cardiovasc Res 115:824, 2019.)
VIDEO A10-1: Pulse pressure
Considerable evidence suggests that pulse pressure serves as an important risk factor for future cardiovascular events. This video clip explains the derivation of pulse pressure and some of the pathophysiology that determines this parameter. (Reproduced with permission from the AnimationMD-CA, Inc.)
VIDEO A10-2: Plaque Instability and Acute Events
Most coronary thromboses result from a physical disruption of the atherosclerotic plaque. This animation explains some of the current concepts of the pathophysiology of atherosclerotic plaque disruption and how it triggers arterial thrombosis. (From P Libby: Changes and challenges in cardiovascular protection: A special CME activity for physicians. Created under an unrestricted educational grant from Merck & Co., Inc. Copyright © 2002, Cardinal Health; used with permission.)
VIDEO A10-3: The Lipoprotein Menagerie
The lipid profile confers important information regarding cardiovascular risk and the effects of therapies; understanding lipoprotein metabolism provides insight into the pathophysiology of arterial disease. This animation presents the rudiments of lipoprotein metabolism that are important in clinical medicine. (From P Libby: Changes and challenges in cardiovascular protection: A special CME activity for physicians. Created under an unrestricted educational grant from Merck & Co., Inc. Copyright © 2002, Cardinal Health; used with permission.)
VIDEO A10-4: Pathogenesis of the Atherosclerotic Plaque and Acute Coronary Syndromes
Physicians now understand the generation of atherosclerotic plaques as a dynamic process involving an interchange between cells of the artery wall, inflammatory cells recruited from blood, and risk factors such as lipoproteins. This animation reviews current thinking about how risk factors alter the biology of the artery wall and can incite initiation and progression of atherosclerosis. It also discusses the importance of inflammation in these processes and portrays the role of inflammation in plaque disruption and thrombosis. Finally, this animation depicts the concept of stabilization of atherosclerotic plaques by interventions such as lipid lowering. (From P Libby: Changes and challenges in cardiovascular protection: A special CME activity for physicians. Created under an unrestricted educational grant from Merck & Co., Inc. Copyright © 2002, Cardinal Health; used with permission.)
VIDEO A10-5: Atherogenesis
This video clip highlights some of the current thinking about mechanisms of atherogenesis. (From P Libby: Changes and challenges in cardiovascular protection: A special CME activity for physicians. Created under an unrestricted educational grant from Merck & Co., Inc. Copyright © 2002, Cardinal Health; used with permission.)
VIDEO A10-6: Metabolic Syndrome, Diabetes and Atherogenesis
A number of important cardiovascular risk factors tend to cluster in a pattern that has been described by some as metabolic syndrome. Although controversy persists regarding whether cardiovascular risk due to these factors is additive or synergistic, their clinical importance is growing. This animation discusses some of the metabolic derangements that underlie metabolic syndrome. (From P Libby: Changes and challenges in cardiovascular protection: A special CME activity for physicians. Created under an unrestricted educational grant from Merck & Co., Inc. Copyright © 2002, Cardinal Health; used with permission.)