Vascular Pathobiology: Atherosclerosis and Large Vessel Disease

Large vessel arterial disease may be regarded as atherosclerotic or nonatherosclerotic; the latter includes less common diseases related to known genetic abnormalities, degenerative conditions, and specific immune and infectious processes. Atherosclerosis is a chronic vascular disease initially involving the intima of elastic and larger muscular arteries and characterized by the presence of fibroinflammatory lipid plaques (atheromas). It is a leading cause of morbidity and mortality in North America and results in major economic and health burden across the globe. Atherogenesis is a function of the interplay between an individual’s genetic disposition, environmental exposure, and living habits adopted by the individual. The intima, media, and adventitia are involved in pathogenesis as well as the associated perivascular adipose tissue. Resident cells, circulating cells, and stem/progenitor cells are involved in regulation of the atherogenic process. The pathogenesis is complex, multifactorial, and the relative importance of specific genetic and external factors vary among individuals. Growth of a plaque is a chronic dynamic inflammatory process involving innate and adaptive immunity with superimposed acute events. The most serious acute events are plaque rupture and atherosclerotic aneurysm rupture. Interactions between cells and matrix of the artery and serum constituents, leukocytes, platelets, and physical forces regulate the formation and growth of the fibroinflammatory lipid plaque. Regulation of gene expression in the plaque occurs through the DNA sequence and by miRNAs and other epigenetic processes that regulate translation and posttranslational events. There are dynamic molecular interactions in the microenvironment of the plaque among gene products that participate in inflammation, lipid metabolism, extracellular matrix remodeling, and thrombosis. Both local biological events at the blood–endothelial interface and systemic factors are involved. Thrombosis is associated with plaque growth, lumen occlusion, and plaque rupture. Focal plaque growth leads to the development of luminal stenosis, complicated plaques, and weakening of some vessel walls. Complicated plaques may become destabilized and lead to plaque rupture and occlusive thrombosis. Organs with atherosclerosis in the supply arteries develop clinical disease, including ischemic heart disease, stroke, and peripheral vascular disease. Known environmental and genetic risk factors are associated with increased disease. Risk reduction through risk stratification and treatment is a successful approach to prevention and treatment of atherosclerotic disease.