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[Atherosclerosis--search for a new entity]
1Institut für Pathologie, Johannes Gutenberg Universität Mainz.
Insights
Atherosclerosis, a vascular disease, progresses through distinct phases involving inflammatory cell infiltration, smooth muscle cell proliferation, and lipid core formation. Plaque rupture can lead to severe cardiovascular events like heart attack and stroke.
Area of Science:
- Cardiovascular Biology
- Pathology
- Immunology
Context:
- Atherogenesis is a progressive disease affecting medium and large arteries.
- Early lesions, characterized by monocyte adhesion and macrophage foam cell formation, are prevalent in youth.
- Lesion progression involves smooth muscle cell proliferation and extracellular matrix deposition, leading to lumen compromise.
Purpose:
- To elucidate the multi-phase pathogenesis of atherosclerosis.
- To explore the cellular and molecular mechanisms driving lesion development and progression.
- To discuss current hypotheses regarding the multifactorial etiology of atherosclerosis, including the 'response to injury' model.
Summary:
- Atherosclerosis progresses through three phases: initial inflammatory lesions with foam cells, smooth muscle cell proliferation, and necrotic lipid core formation with fibrous caps.
- Plaque rupture, triggered by inflammation or mechanical stress, leads to thrombosis and clinical events such as myocardial infarction and stroke.
- Research challenges include the decades-long silent progression and limitations of animal models, with ongoing debate on the roles of LDL, immune responses, infections, and genetics.
Impact:
- Understanding atherosclerosis pathogenesis informs the identification of established risk factors like hypercholesterolemia, hypertension, and diabetes.
- Knowledge of atherosclerosis mechanisms supports interventions including lifestyle changes, exercise, and pharmacological control of risk factors.
- Atherosclerosis is redefined from a degenerative process to a complex, multifactorial disease with identifiable risk and protective factors.
Abstract:
Atherogenesis is a disease of middle-sized and large caliber blood vessels that can be divided into three major phases. The initial lesions of early atherosclerosis are characterized by the adhesion and subendothelial emigration of blood-borne monocytes, which differentiate into macrophages and provide the morphological basis for the formation of foam cells and fatty streak lesions. These lesions are found in most children and teenagers in industrialized nations. The next key event in atherogenesis is the proliferation of smooth muscle cells within the intima and media, resulting in the gradual compromise of the vessel lumen. Myofibroblastic cells also contribute to lesion growth through the production of excessive amounts of extracellular matrix. Such lesions are clinically silent unless progression to the next phase continues: the lesions degenerate, forming a mostly necrotic "lipid core" consisting of extracellular lipid, cholesterol crystals, inflammatory cells and necrotic debris. A fibrous cap is formed which prevents the interaction of blood cells, particularly of platelets with the highly proaggregatory material found in the lipid core. However, continuous inflammatory activity and/or heightened mechanical stress (i.e. in hypertension) tends to weaken the fibrous caps. Eventually, plaque rupture ensues, platelets aggregate, and the lesions become clinically manifest in such dramatic events as myocardial infarction, stroke, or mesenteric ischemia. Research into lesion formation and progression is limited by the fact that lesions develop in silence over many decades and that animal models only incompletely model the situation in humans. Most currently debated concepts accept the "response to injury" hypothesis formulated by the late Russell Ross and the multifactorial nature of atherogenesis. The discussion today circles around the relative contributions of low density lipoproteins (oxidized or enzymatically modified LDL?), the immune response (adaptive or innate?), infectious agents (CMV, chlamydia pneumoniae?), and/or hereditary factors, to name only a few of the most widely debated concepts. Irrespective of the outcome of this pathomechanistic discussion, the knowledge of established risk factors (hypercholesterolemia, hypertension, diabetes, smoking, etc.) and protective interventions (lifestyle changes, physical exercise, "healthy" diets, effective dietary and pharmacological control of hyperglycemia, blood pressure or hyperlipidemia) has helped to define atherosclerosis as a "new entity" that has little to do with the archaic concept of a "degenerative" vessel disease.