Complex cellular and molecular interactions drive the process of atherothrombosis that results from a prolonged course of different interactions, activations, and passivations along variable periods of time. Initially, the process is clinically silent (subclinical atherosclerosis) and becomes fully apparent when the atherosclerotic process is complicated with thrombosis and clinical events are initiated. Atherosclerosis is the main underlying cause of coronary artery disease, peripheral artery disease, and cerebrovascular disease. Cardiovascular risk factors act as accelerators of a process initiated by endothelial dysfunction, with consequent permeability alterations, induction of cytokine expression, loss of resistance against thrombocyte deposition, and impaired release of profibrinolytic products. A dysfunctional endothelium located in hemodynamically or rheologic compromised areas promotes the internalization of lipids that accumulate in the intimal layer and attract innate immune cells (eg, monocytes) that become activated and, by the local exposure of modified protein epitopes, damage-associated molecular patterns (DAMPs), and oxidized lipids species, initiate the second phase of atherogenesis, with mild structural modifications of the arterial wall. The process progresses with the participation of dendritic cells; adaptive immune cells; local inflammation; vascular smooth muscle cell (VSMC) activation; extracellular matrix degradation; and cell apoptosis, senescence, and necrosis, and, ultimately, the vascular wall undergoes significant structural modifications with a decline in VSMCs and presence of fragile or hemorrhagic neovessels and calcified nodules. These plaques usually protrude into the lumen and are prone to rupture. Disruption of atherosclerotic lesions exposes thrombogenic surfaces rich in tissue factor and matrix proteins that induce fibrin deposition and platelet adhesion, activation, and aggregation. The resulting thrombi can be mural or occlusive depending on different factors that are not fully known. These thrombi can induce homing of leucocytes and even progenitor cells. Released extracellular vesicles (mainly microvesicles), earlier considered to be mere biomarkers of the event, have been found to have a significant role in cellular crosstalk and transference of cellular material in a paracrine fashion. This chapter reviews our current understanding of the pathophysiological mechanisms involved in atherothrombosis and analyzes how this process may be prevented and modulated.
Acronyms and Abbreviations
ABC, adenosine triphosphate (ATP)-binding cassette; ACS, acute coronary syndrome; ADP, adenosine diphosphate; ADAM, a disintegrin and metalloprotease with thrombospondin motif; AMP, adenosine monophosphate; AMPK, adenosoine monophosphate kinase; CABG, coronary artery bypass graft; CAD, coronary artery disease; CE, cholesterol ester; CI, confidence interval; CRP, C reactive protein; CHD, coronary heart disease; COX-1, cyclooxygenase-1; CVD, cardiovascular disease; DAG, diacylglycerol; DC, dendritic cells; ECM, extracellular matrix; eNOS, endothelial nitric oxide synthase; ESC, European Society of Cardiology; EV, extracellular vesicle; GP, glycoprotein; GPI, glycoprotein inhibitors; HDL, high-density lipoprotein; HF, heart failure; HIV, human immunodeficiency virus; hsCRP, high-sensitivity C-reactive protein; ICAM, intercellular adhesion molecule; IFN, interferon; IL, interleukin; KLF-4, Kruppel-like factor-4; LFA-1, lymphocyte-associated antigen-1; LDL, low-density lipoprotein; Lp(a), lipoprotein (a); LMWH, low-molecular-weight heparin; LOX1, lectin-like oxLDL receptor 1; LRP-1, lipoprotein receptor-related protein-1; MAC-1, macrophage antigen-1; MCP, monocyte chemoattractant protein; miRNA, microRNA, MI, myocardial infarction; mmLDL, minimally modified LDL; MMP, matrix metaloproteins; MPO, ...