Endothelium-derived nitric oxide (EDNO) synthesis and action. In endothelial cells, a constitutive membrane-associated NO synthase (eNOS) catalyzes the conversion of the amino acid L-arginine to NO and L-citrulline. eNOS cofactors include FAD (flavin adenine dinucleotide), NADPH (nicotinamide adenine dinucleotide phosphate), TH4 (tetrahydrobiopterin), and calcium. Endothelial synthesis of NO is tightly controlled and linked to changes in ionized calcium concentration. Several agonists, including acetylcholine, bradykinin, substance P, and platelet-derived serotonin, act on specific membrane receptors that trigger cytosolic calcium release and eNOS activation. Increased shear stress from enhanced blood flow also serves as an important stimulus for NO production. Nitric oxide modulates basal vascular tone, and exerts a dilator effect on vascular smooth muscle through activation of soluble guanylyl cyclase and consequent increase in intracellular cyclic 3',5'-guanosine monophosphate (cGMP), which also mediates NO-dependent inhibition of platelet activation. Individuals with coronary risk factors or atherosclerosis demonstrate impaired shear stress- and agonist-induced endothelium-dependent vasodilation. Other actions of NO include inhibition of monocyte adhesion and smooth muscle cell proliferation. GTP (guanosine 5'-triphosphate).

The response-to-injury hypothesis of atherosclerosis. In response to mechanical injury or exposure to atherogenic stimuli, such as oxidized LDL, diabetes mellitus, severe hyperhomocystinemia, and cigarette smoking, endothelial cells express adhesion molecules and elaborate growth factors that lead to recruitment of leukocytes in an inflammatory response to injury. Leukocytes adhere and migrate into the vessel wall, localize subendothelially, and develop into lipid-laden macrophages (foam cells). Foam cells, in turn, release growth factors and cytokines that promote recruitment of smooth muscle cells and stimulate neointimal proliferation, continue to accumulate lipid, and support endothelial cell dysfunction. Collectively, these events promote the development of a lipid-rich atheromatous lesion. Subsequent denudation of the endothelium exposes circulating platelets and coagulants to the underlying matrix, thereby initiating thrombosis, and triggering a cascade of events leading to a fibroproliferative lesion and luminal narrowing.

Intimal surface of right coronary artery from a 32-year-old man. Atherosclerotic lesions are advanced when the accumulation of lipid, cells, and matrix are associated with disorganization, repair, and thickening of the intima and deformity of the arterial wall. Type IV lesions, also called atheromas, are advanced lesions in which extracellular lipid occupies a well-defined and extensive area in the intima, called the lipid core, that develops by coalescence of smaller isolated pools of extracellular lipid. When seen in younger people, atheromas occur in areas of previous adaptive intimal thickening. Although atheromas are raised lesions, they do not necessarily result in significant luminal occlusion. Microscopically, the extracellular lipid in atheromas displaces and replaces smooth muscle cells and extracellular matrix.

A cross-section of coronary artery that has significant luminal obstruction by an atheroma. A lipid-rich core can be seen in the center of the lesion.

Rupture of a plaque. Note that the endothelium is broken exposing the underlying tissue to the blood and starting the clotting cascade, in the same way blood clots when blood vessels in the skin are cut. Plaque rupture is cut inside an artery.

Using the technique of intravascular ultrasound (IVUS) in hearts removed for transplantation from accident victiims of all ages in the US, investigators at the Cleveland Clinic found advanced atheroscerotic plaque in one sixth of teenagers. By age 50, 85% of hearts had advanced plaque. None of these subjects had symptoms or had yet had a heart attack but were clearly at risk for one because the plaque was buried in the arterial wall which had undergone compensatory dilation. Obviously prevention of atherosclerosis must begin in childhood. Unless one is foolish enough to believe that statins should be given to every child in the Western world, prevention means adoption of a non-atherogenic lifestyle from weaning.