Evolving concepts in the pathophysiology of atherosclerosis: From endothelial dysfunction to thrombus formation through multiple shades of inflammation

Atherosclerosis is the anatomo-pathological substrate of most cardio, cerebro and vascular diseases such as acute and chronic coronary syndromes, stroke and peripheral artery diseases. The pathophysiology of atherosclerotic plaque and its complications are under continuous investigation. In the last 2 decades our understanding on the formation, progression and complication of the atherosclerotic lesion has greatly improved and the role of immunity and inflammation is now well documented and accepted. The conventional risk factors modulate endothelial function determining the switch to a proatherosclerotic phenotype. From this point, lipid accumulation with an imbalance from cholesterol influx and efflux, foam cells formation, T-cell activation, cytokines release and matrix-degrading enzymes production occur. Lesions with high inflammatory rate become vulnerable and prone to rupture. Once complicated, the intraplaque thrombogenic material, such as the tissue factor, is exposed to the flowing blood, thus inducing coagulation cascade activation, platelets aggregation and finally intravascular thrombus formation that leads to clinical manifestations of this disease. Nonconventional risk factors, such as gut microbiome, are emerging novel markers of atherosclerosis. Several data indicate that gut microbiota may play a causative role in formation, progression and complication of atherosclerotic lesions. The gut dysbiosis-related inflammation and gut microbiota-derived metabolites have been proposed as the main working hypothesis in contributing to disease formation and progression. The current evidence suggest that the conventional and nonconventional risk factors may modulate the degree of inflammation of the atherosclerotic lesion, thus influencing its final fate. Based on this hypothesis, targeting inflammation seems to be a promising approach to further improve our management of atherosclerotic-related diseases.