Coronary Artery Disease (CAD) is a progressive condition characterized by the hardening and narrowing of the coronary arteries, which supply oxygenated blood directly to the heart muscle. The pathophysiology of CAD is a complex, long-term inflammatory response within the artery wall that unfolds over many years. This process begins with subtle damage to the inner lining of the blood vessel and progresses through distinct phases of plaque formation and structural change. Understanding this sequence provides insight into how chronic vascular injury ultimately leads to restricted blood flow to the myocardium.
Endothelial Dysfunction: The Initial Damage
The development of CAD begins with the innermost layer of the artery, a single sheet of cells called the endothelium. This layer normally maintains a non-stick, anti-inflammatory, and vasodilatory environment, but its function can be compromised by various chronic stressors. Factors like high blood pressure, toxins from smoking, and elevated glucose levels generate oxidative stress, which directly injures the endothelial cells. This injury causes the endothelium to transition from a healthy, protective barrier to a dysfunctional state.
A key change in this dysfunctional state is an imbalance in the production of vasoactive molecules, such as a reduction in nitric oxide (NO). Nitric oxide is a potent vasodilator, and its loss leads to an increased tendency for the artery to constrict. The compromised endothelium also becomes more “sticky,” expressing adhesion molecules that promote the binding and entry of immune cells into the artery wall. This loss of integrity and shift toward a pro-inflammatory environment sets the stage for plaque formation.
Atherogenesis: From Injury to Fatty Streak
Following the initial endothelial injury, atherogenesis begins with the infiltration of lipids into the subendothelial space, the layer just beneath the damaged lining. Low-density lipoprotein (LDL) particles become trapped within this space, interacting with matrix components. Once trapped, these LDL particles are chemically modified, primarily through oxidation, which makes them highly inflammatory and recognizable by the immune system.
The oxidized LDL triggers the recruitment of monocytes, a type of white blood cell, from the bloodstream. These monocytes penetrate the dysfunctional endothelium and move into the artery wall, where they differentiate into scavenging cells known as macrophages. Macrophages ingest the foreign, oxidized LDL in large quantities.
As macrophages gorge on the lipid, they swell dramatically and take on a characteristic foamy appearance, earning them the name “foam cells.” The accumulation of these lipid-laden foam cells beneath the endothelium creates the first visible lesion of atherosclerosis, termed the fatty streak. Although a fatty streak is a sign of early disease, it does not significantly impede blood flow on its own, representing a reversible phase of the condition.
Plaque Maturation and Arterial Narrowing
The fatty streak gradually transforms into a complex, mature atherosclerotic plaque through structural modifications and cellular activities. In response to inflammatory signals, specialized smooth muscle cells (SMCs) migrate from the middle layer of the artery wall (the media) to the inner layer (the intima). These migrating SMCs proliferate and synthesize large amounts of extracellular matrix, notably collagen. The collagenous matrix forms a protective layer, the fibrous cap, which covers the accumulated lipid and foam cells below.
Beneath this cap lies a core of dead foam cells, lipid debris, and cholesterol crystals, forming a necrotic core. As the plaque matures, it undergoes calcification, where calcium deposits are incorporated into the lesion. Calcification is driven by the transdifferentiation of SMCs into cells resembling bone-forming cells, solidifying the plaque structure. The continued accumulation of these components causes the plaque to expand, progressively protruding into the artery lumen. This expansion leads to chronic arterial narrowing, or stenosis, which limits blood flow to the heart muscle, causing insufficient blood supply (ischemia) and chronic symptoms.
The Mechanism of Acute Heart Attack
The transition from chronic, stable narrowing to an acute heart attack hinges on the stability of the mature plaque. Unstable plaques often have a thin fibrous cap covering a large, soft, lipid-rich necrotic core. Mechanical stress from blood flow, compounded by inflammation, can cause this thin cap to tear or rupture. In some cases, the surface layer may simply erode without a deep tear.
Plaque rupture or erosion immediately exposes the contents of the necrotic core to the flowing blood. This core contains highly thrombogenic material, most notably a protein called tissue factor. The contact between this material and the blood triggers the activation of the body’s clotting system. Platelets instantly aggregate at the site of injury, and the coagulation cascade is initiated, leading to the swift formation of a blood clot, or thrombus. The sudden, total occlusion of blood flow causes an acute lack of oxygen to the downstream heart muscle, resulting in a myocardial infarction.