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 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 the “metabolic syndrome.” In the wake of increasing obesity worldwide, these features of the lipoprotein profile require renewed focus. Several of the animations in this collection discuss the concept of the 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.
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. (With permission from the Academy for Health Care Education.)
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.
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.
VIDEO A10-4: Pathogenesis of the Atheroscleratic Plaque and Acute Coronary Syndromes
Formation and complication of atherosclerotic plaques. 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.
VIDEO A10-5: Atherogenesis.
This video clip highlights some of the current thinking about mechanisms of atherogenesis.
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 the 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 the metabolic syndrome.
How aggressive lipid lowering alters coronary atheromata. This figure depicts how rigorous low-density lipoprotein (LDL) lowering affects human arterial plaques as shown by imaging modalities. The lumen changes little, the lipid core becomes smaller, and the proportion of the plaque composed of fibrous tissue increase. The amount of calcification actually increases with statin treatment, a point to keep in mind when considering coronary artery scores. (From P Libby: How does lipid lowering prevent coronary events? New insights from human imaging trials. Eur Heart J 36:472, 2015.)
Coronary artery cross-sections. Various mechanisms can cause coronary thrombosis that results from superficial erosion vs fibrous cap fissure. This diagram represents cross-sectional views of human coronary arteries. On the left, thrombosis provoked by erosion causes a “white” thrombus complicating a lesion rich in proteoglycan and glycosaminoglycan. Endothelial cell desquamation uncovers basement membrane collagen that can activate platelets. Polymorphonuclear leukocytes (PMN) then accumulate and cause a “second wave” of local injury, and amplification and propagation of clotting, in part due to formation of neutrophil extracellular traps (NETs). Erosion may contribute more frequently to non-ST-segment elevation myocardial infarction (NSTEMI) than to STEMI. The image on the right portrays thrombosis resulting from rupture of a thin-capped fibroatheroma. Such thrombi often have a “red” fibrin-rich character. Macrophage-derived tissue factor provokes clotting complicating plaque rupture. (From P Libby: Superficial erosion and the precision management of acute coronary syndromes: not one-size-fits-all. Eur Heart J: 38:801, 2017.)
A. “Two-Hit” concept of thrombosis caused by plaque erosion. This figure depicts a longitudinal section of a coronary artery that harbors an extracellular matrix-rich atheroma. The dark brown represents deposits of extracellular matrix macromolecules abundant in eroded plaques including hyaluronic acid. Instigators of damage to the endothelium include pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and other activators of TLR2, and innate immune receptor that we have implicated in superficial erosion. Various inflammatory stimuli can impair endothelial cell viability. Proteolytic enzymes including the matrix metalloproteinases can digest basement membrane components to which endothelial cells adhere. Type IV collagenases (MMP-2 and MMP-9) can thus favor detachment of endothelial cell to the underlying basement membrane, rich in type IV collagen. When a patch of endothelial cells slough or die they can form tissue factor bearing microparticles that stimulate clotting. Recruitment of granulocytes provides a source of the proinflammatory and thrombogenic mediator MRP-8/14 and of reactive oxygen species such as hypochlorite produced by myeloperoxidase (MPO), as well as superoxide anion (O2−). We hypothesize that neutrophil numbers increase secondarily, rather than cause initial intimal injury. Activated polymorphonuclear leukocytes can release strands of DNA and histones giving rise to neutrophil extracellular traps (NETs). NETs can extend thrombosis. Local activation of neutrophils and platelets augments the availability of cytokines including interleukin-6 and RANTES. Platelets also elaborate plasminogen activator inhibitor-1 (PAI-1) that blocks fibrinolysis. (With permission from T Quillard et al: TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. Eur Heart J 36:1394, 2015.)
Risk factors and their modification can regulate atherosclerosis by altering inflammation. Risk modifiers alter atherosclerosis by regulating inflammation as determined by changes in biomarkers. The selected risk factors at the top elicit various pro-inflammatory cytokines including interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α). These mediators can accelerate atherogenesis by direct effects on the lesions, and also trigger the release of acute phase reactant from hepatocytes signaled by interleukin-6, that we have dubbed the “messenger cytokine.” Products of the acute phase response include fibrinogen and plasminogen activator inhibitor-1 (PAI-1) that regulate thrombosis and clot stability and also biomarkers of inflammation such as C-reactive protein (CRP) or serum amyloid A (SAA) that although not causal risk factors can serve as clinically useful gauges of inflammatory status. Factors that may lower risk of atherosclerotic events such as dietary factors or physical activity may mitigate inflammation as monitored by CRP. (From P Libby, F Crea: Clinical implications of inflammation for cardiovascular primary prevention. Eur Heart J 31:777, 2010.)
Rheumatic diseases accelerate atherosclerotic risk. Rheumatologic disorders elevate systemic inflammation and can thus potentiate atherothrombosis. (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.)
Rheumatologic conditions can potentiate the pathogenesis of atherosclerosis. Patients with inflammatory rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosis, and various vasculitides can have a higher burden of traditional risk factors for atherosclerosis than well individuals. Abbreviations: Ab, antibody; ANCA, antineutrophil cytoplasmic antibody; dsDNA, double-stranded DNA; CCP, cyclic citrullinated peptide; EC, endothelial cells; IFN, interferon; FcγR, Fc gamma receptor; HOCL, hypochloride; MPO, myeloperoxidase; ROS, reactive oxygen species; T reg, regulatory T lymphocytes. (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.)
From Peter Libby, MD: 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.