Atherosclerosis: Lipid-lowering drugs for cardioprotection

Lowering LDL cholesterol in the blood reduces the risk of cardiovascular events. Although effective medications are available, only a small proportion of patients at high cardiovascular risk achieve the desired target. Therefore, combination therapy is advisable as the risk profile increases.

Reducing excess weight, increasing exercise, and a moderate diet are part of the basic program of lipid-lowering therapy. However, many patients also require lipid-lowering medication. / © Shutterstock/Africa Studio

Cardiovascular diseases resulting from atherosclerosis remain the most common cause of death in Germany. One in three adults in Germany has high cholesterol levels. This is one of the most important risk factors for atherosclerosis and thus for coronary heart disease, heart attack, stroke, and peripheral arterial disease.

Atherosclerosis is a chronic inflammatory disease of medium-sized arteries characterized by the formation of lipid-rich plaques in the intima. Key pathophysiological processes include endothelial dysfunction, lipid accumulation, chronic inflammation, and remodeling of the vascular wall (Figure 1). The disease usually develops asymptomatically over decades and often only becomes apparent through subsequent clinical events such as myocardial infarction, ischemic stroke, or peripheral arterial disease (PAD).

Atherosclerosis initially develops at hemodynamically stressed sites such as vascular junctions, where turbulent flow conditions prevail. Cholesterol-rich low-density lipoprotein (LDL) particles penetrate the subendothelial space and bind to proteoglycans in the extracellular matrix. Endothelial-damaging risk factors such as hypertension, diabetes mellitus, and smoking abuse promote this penetration.

The LDL particles undergo mild oxidation by reactive oxygen species in the subendothelium. Oxidized LDL induces the adhesion of monocytes to the endothelium, which subsequently migrate into the subendothelium and differentiate into macrophages, which in turn take up oxidized LDL and become cholesterol-laden foam cells. Early fatty streak-like lesions develop in the lumen of the arteries.

Perishing lipid-overloaded foam cells and infiltrating T lymphocytes secrete pro-inflammatory cytokines such as IL-6, TNF-α, and IFN-γ, which trigger and maintain chronic inflammation in the arteries. In parallel, medial smooth muscle cells dedifferentiate, regain their ability to divide, migrate into the intima, and proliferate there alongside fibroblasts.

Both cell types form components of the extracellular matrix, such as collagen, which contributes to the formation of a plaque-stabilizing cap. This cap covers the central necrotic core of dead foam cells, cholesterol, and cellular debris. The newly formed plaque construct (Figure 1, right) progressively grows into the vessel lumen.