Early atherogenesis: In search of etiology.

Atherosclerosis is a complex chronic inflammatory disease that affects the larger arteries. Early atherogenesis involves a group of pathological processes including endothelial activation and dysfunction, lipoprotein transcytosis and modification, monocyte recruitment and transmigration, and foam cell formation, culminating in fatty streak formation. These processes are mediated by numerous molecules, which could be considered potential diagnostic and therapeutic targets. Atherogenic processes are also driven by several risk factors, including the demographic factors age and sex; family history; dyslipidemia and related chronic lifestyle diseases; unhealthy behaviors related to exercise, diet, alcohol intake, smoking, and sleep; microbial activity; air pollution; and disturbed hemodynamics including low or oscillatory wall shear stress. However, despite our growing knowledge of atherogenesis, the etiology of atherosclerosis remains unsettled. This review first describes early atherogenic processes and their key mediators. The complexity of atherogenesis is then briefly explored to illustrate the uncertainties surrounding the initiation of atherogenesis, including the complex relationships between the evidence-based risk factors identified and atherogenic processes. Finally, the etiology of this important pathology is explored by applying established criteria for causation, including temporality, strength of association, plausibility, and experimental evidence, to the identified risk factors. The review concludes that of all the evidence-based risk factors identified, disturbed wall shear stress is the only one that approximates the criteria for causation, and ends with an overview of the implications.