1. Understanding Cholesterol as a Biological Molecule

Cholesterol is indispensable for human health. It serves as:

• A structural component of cell membranes (ensuring fluidity and integrity)
• A precursor for steroid hormones (e.g., estrogen, testosterone)
• A precursor for vitamin D and bile acids necessary for fat digestion

Before and during our 20s (and sometimes into the early 30s), circulating cholesterol—delivered by lipoproteins such as LDL—is actively utilized in tissue growth and repair. However, after skeletal and organ development stabilize, the physiological need for higher LDL levels declines substantially [1,2]. At that point, persistent elevations in LDL can lead to an increased risk of atherosclerotic disease.

2. The Role of LDL and Atherosclerotic Cardiovascular Disease (ASCVD)

2.1 Why LDL Is Causally Linked to ASCVD

• Infiltration of the Artery Wall: LDL particles can penetrate the endothelium of arteries. Once retained, they undergo oxidation and trigger an inflammatory cascade, driving atherosclerotic plaque formation [3,4].
• Strong Evidence from Multiple Disciplines:
  1. Genetic Studies (Mendelian Randomization): Individuals with genetically lower LDL have substantially reduced ASCVD risk across their lifespan, supporting a causal relationship [5].
  2. Epidemiology & Clinical Trials: Large-scale trials (e.g., CTT meta-analyses, 4S, WOSCOPS) confirm that lowering LDL reduces heart attacks and strokes [3,6].
  3. No “Safe Threshold”: Data suggest a linear relationship between LDL levels and ASCVD events, meaning that risk decreases as LDL goes lower, with no clear cut-point below which harm emerges [7,8].

2.2 Clinical Impact of Elevated LDL

• In 2021, 3.81 million cardiovascular deaths worldwide were attributed to elevated LDL cholesterol [9].
• Each 1 mmol/L (~39 mg/dL) reduction in LDL-C can reduce major vascular events by approximately 20–25% within 5 years [3,10].
• Over multiple decades, the cumulative benefit is even greater, especially when LDL is kept low starting earlier in adulthood [11,12].

3. Other Key Risk Factors: Lipoprotein(a) and Blood Pressure

3.1 Lipoprotein(a)