Surprisingly, atherosclerotic plaques expand outward during much of their existence, rather than impinging on an artery’s blood-carrying channel. This pattern preserves blood flow for quite some time, often for decades. When the plaques do push inward, they restrict the blood channel—a condition called stenosis. Stenosis can impede blood delivery to tissues, especially at moments of greater need, when the arteries would usually expand. When a person exercises or experiences stress, for instance, blood flow through a compromised heart artery can fail to match the increased demand, causing angina pectoris: a feeling of tightness, squeezing or pressure usually under the breastbone. Narrowing in other arteries can cause painful cramping of the calves or buttocks during exertion, symptoms known as intermittent claudication.
SOMETIMES A PLAQUE grows so large that it virtually halts blood flow in an artery and generates a heart attack or stroke. Yet only about 15 percent of heart attacks happen in this way. By carefully examining vessel walls of people who died from heart attacks, pathologists have demonstrated that most attacks occur after a plaque’s fibrous cap breaks open, prompting a blood clot to develop over the break. The plaques most likely to fracture possess a thinned cap, a large lipid pool and many macrophages, and their vulnerability stems, as in earlier stages of atherosclerosis, from inflammation.
The integrity of the fibrous covering depends largely on steel-strong collagen fibers made by smooth muscle cells. When something causes inflammation to flare in a relatively quiet plaque, mediators of the process can compromise the cap in at least two ways. My laboratory has shown that these inflammatory mediators can stimulate macrophages to secrete enzymes that degrade collagen, and they can inhibit smooth muscle cells from extruding the fresh collagen required to repair and maintain the cap.
Clots form when blood seeps through a fissure in the cap and encounters a lipid core teeming with proteins able to facilitate blood coagulation. For example, molecules on T cells in the plaques spur foam cells to manufacture high levels of tissue factor, a potent clot inducer. Circulating blood itself contains precursors of the proteins involved in the cascade of reactions responsible for clot formation. When blood meets tissue factor and other coagulation promoters in a plaque’s core, the clotting precursors jump into action. Our bodies produce substances that can prevent a clot from materializing or can degrade it before it causes a heart attack or stroke, but inflamed plaques release chemicals that impede the innate clot-busting machinery.
If a clot does get cleared naturally or with the aid of drugs, the healing process may kick in once again, restoring the cap but also further enlarging the plaque by forming scar tissue. Indeed, considerable evidence suggests that plaques grow in fits and starts, as triggers of inflammation come and go and as clots emerge and dissolve but leave scars.
The new picture of atherosclerosis explains why many heart attacks seem to come from out of the blue: the plaques that rupture do not necessarily protrude very far into the blood channel and so may not cause angina or appear prominently on images of the channel. The new view also clarifies why therapies that focus on widening the blood passage in semioccluded arteries (balloon angioplasty or insertion of wire-cage stents) or on surgically creating a bypass can ease angina yet frequently fail to prevent a future heart attack. In such cases, the danger may lurk elsewhere, where a plaque causes less narrowing but is more prone to rupturing. Sadly, even when stenosis is the problem, treated arteries often become reoccluded fairly rapidly—apparently in part because the treatments can elicit a robust inflammatory response.