Atherosclerosis : Understanding Pathogenesis & Challenge for Treatment

Atherosclerosis is a chronic inflammatory disease that affects medium and large-sized arteries. It begins after birth and the progression depends on several factors - traditional triad: hypertension, hyperlipidemia and diabetes mellitus, then age, sex, smoking and sedentary life-style. At the beginning atherosclerosis is asymptomatic and we cannot estimate appropriately its frequency, but its complications - coronary artery diseases, cerebrovascular diseases, peripheral arterial diseases, which occur late, are responsible for more than half of the yearly mortality in the world. Unfortunately, sudden cardiac death may be the first clinical manifestation. The incipient event is endothelial dysfunction, as a result of injury, caused by high level of cholesterol [especially w-density-lipoprotein LDL], hyperglycemia, hypertension, smoking, infectious agents, and toxins. Endothelial cells overexpress adhesion molecules - vascular cell adhesion molecule-1 [VCAM-1] and increases recruitment of inflammatory cells - monocytes [Mo], T-cells and subsequent release of monocyte chemo-attractant protein-1 [MCP-1] that results in additional leucocytes recruitment. Injured endothelium allows migration of inflammatory cells that release cytokines and lipids into the intima. That leads to cytokine-mediated progression of atherosclerosis and oxidation of LDL. Macrophages [MP] take up oxi-LDL and form foam-cell. They have metabolic activity and produce cytokines, proliferation of smooth muscle cells and formulate athero-fibrose plaque. Atherosclerotic plaque is composed of superficial layer - fibrose cap and lipid core, that consists of foam cells, extracellular lipid and necrotic cellular debris. It progresses as a result of accumulation of lipid and proliferation of smooth muscle cells and results in luminal narrowing of the arteries which leads to compromised blood and oxygen supply to the tissues. The gradually growing atherosclerotic plaques have thick fibrose cap and are stable. They cause symptoms of stable angina. Rapidly growing plaques cause unstable coronary artery disease. These plaques are mainly composed of lipids and have tiny fibrose cap that is prone to fissuring or rupture. Intraplaque hemorrhage from microvessels in plaque initiate platelet adhesion and activation of coagulation cascade that leads to platelet thrombus formation, i.e. promote thrombogenesis. Knowledge of the pathogenesis of the atherothrombosis modifies the diagnostic and therapeutic approach. Conclusion: Attention should be focused on the management of three points: 1. Endothelial dysfunction [correction of modified risk factors: hypertension, hyperlipidemia, diabetes mellitus, life-style-smoking, physical activity and food], 2. Atherosclerosis [modification of the inflammatory cascade, i.e. elimination of inflammatory pathways and inhibition of oxidation of LDL], 3. Thrombogenesis [inhibition of platelet adhesion, activation and aggregation].