Atherosclerosis: Pathophysiology

Atherosclerosis is characterized by the accumulation of fatty plaques within blood vessels, specifically in the tunica intima, which is composed of endothelium, connective tissue with a basement membrane, and an internal elastic lamina. Beyond the intima, the tunica media is primarily made up of smooth muscle, while the tunica externa or adventitia houses the vasa vasorum that perfuse the outer two-thirds of the tunica media.

The disease is often multifactorial. A family history stands as the most crucial non-modifiable risk factor. Modifiable risk factors include hypercholesterolemia, where total cholesterol is the sum of LDL, HDL, and VLDL; hypertriglyceridemia, often linked to very low-density lipoproteins (VLDL); diabetes, leading to dysfunctional lipid metabolism and elevated LDL, with increased insulin levels potentially intensifying inflammation; hypertension, inducing endothelial injury; and smoking, causing further endothelial damage. Elevated homocysteine levels, often due to low levels of folate or vitamin B12, serve as additional risk factors. Crucially, increased levels of LDL boost the risk, while increased HDL levels, which transport cholesterol from peripheral tissues to the liver, are protective. For women, the advent of menopause amplifies the risk because of the diminishing protective effects of estrogen.

The pathogenesis of atherosclerosis is initiated by endothelial injury, which sets off a prothrombotic state due to increased endothelin and tissue factor. This injury prompts an upregulation of leukocyte adhesion (LAD) molecules such as ICAM, VCAM, and selectin, leading to leukocyte adhesion and activation. As a response to injury, macrophages stick to and migrate into the vessel wall, and platelets aggregate and activate at the damage site. Further, LDL particles containing cholesteryl esters move into the intima. In the presence of oxygen free radicals, formed by macrophages and local endothelial cells, these LDLs become oxidized. Subsequently, macrophages phagocytose these oxidized LDLs, forming foam cells. Accumulation of these foam cells beneath the endothelium results in the formation of fatty streaks, which are almost ubiquitous in individuals older than 10 years.

These foam cells release cytokines & chemokines, instigating the migration of T-cells to the intima. This, combined with the continuous aggregation and activation of platelets that release more cytokines and chemokines, creates a cycle of chronic inflammation pivotal to the progression of atherosclerosis. The resultant accumulation of inflammatory cells leads to intimal thickening.

In this milieu, smooth muscle cells from the tunica media transition into the intima. Altered by cytokines and growth factors, these cells gain the capacity to phagocytose LDL and cholesterol. Additionally, these transformed smooth muscle cells produce excessive amounts of collagen and other extracellular matrix proteins, culminating in the creation of a fibrous capsule over the lipid core. This lipid core contains areas of necrosis with calcification, cholesterol crystals, oxidized LDL, and cellular debris due to foam cell and smooth muscle apoptosis. Within these plaques, new blood vessels form, and macrophages along with smooth muscle cells produce metalloproteinases which digest the extracellular matrix, including the fibrous cap.

Advanced atherosclerotic plaques can instigate cystic medial necrosis, characterized by significant thickening of the intima and media, leading to necrosis of medial smooth muscle cells. Such plaques also increase the risk of aneurysm formation, often as a consequence of the cystic medial necrosis. As plaques continue to grow, they can lead to vessel stenosis. A critical stenosis arises when a plaque obstructs over 70% of the vessel lumen, precipitating clinical conditions like angina, transient ischemic attacks (TIA), claudication, and renal artery stenosis.