In the dissecting room a yellow spot on the aortic intima looks like fat that has "settled". It is a convenient metaphor and bad physiology. The spot is not a sediment from the lumen but the result of low-density lipoprotein particles having crossed the endothelium, been retained in the intima and triggered a cascade that ESC/EAS 2025 describes in a single sentence: the accumulation of atherogenic lipoproteins triggers inflammatory responses that lead to the formation and progression of plaque.
Low-density lipoprotein (LDL) is a particle that carries cholesterol in the blood; its structural protein is apolipoprotein B-100 (ApoB). One LDL particle contains one ApoB molecule. Therefore the ApoB concentration reflects the number of atherogenic particles, not only the mass of cholesterol in them. LDL cholesterol (LDL-C) is the cholesterol contained in these particles; lowering it remains the main goal of preventing atherosclerotic events in ESC/EAS 2019 and in the 2025 focused update.
Why it is a cause and not a marker. A marker moves together with the disease, but correcting it does not change the outcome. A cause changes the outcome when it is removed. In 2010 the Cholesterol Treatment Trialists' Collaboration pooled individual data from about 170 000 participants in 26 randomised statin trials (Lancet 2010;376:1670–1681, PMID 21067804). For each 1.0 mmol/L reduction in LDL-C, the risk ratio for major vascular events (myocardial infarction, revascularisation, stroke) was 0.78 (95% CI 0.76–0.80), that is, a relative reduction of about 22%. All-cause mortality fell by 10% per 1.0 mmol/L (RR 0.90; 95% CI 0.87–0.93). The effect persisted even in those whose LDL-C on the less intensive regimen was already below 2 mmol/L. This is the logic of "the lower, the better" within the studied range: not a slogan, but proportionality measured in RCTs.
The 2025 Focused Update restates the same proportionality in clinical language. The authors assume an average relative risk reduction of about 20% for each 1 mmol/L reduction in LDL-C. Hence the practical consequence: for a person with an absolute 10-year risk of 20%, lowering LDL-C by 1 mmol/L reduces the risk to about 16% (a relative 20% of 20% is 4 absolute percentage points). The same reduction in a person with a 10% risk corresponds to a fall to 8% (2 absolute points). The same relative reduction yields a different absolute benefit. This is why the intensity of therapy in the guidelines is tied not to "how bad the test is" but to the category of total risk.
The boundary of the lesson. The course does not claim that "the lower the LDL-C, the better" without a floor has been proven for any number in any person. CTT describes the range achieved in statin trials. Lower values in the PCSK9 inhibitor programmes (FOURIER: Sabatine M.S. et al., N Engl J Med 2017;376:1713–1722, 27 564 patients with ASCVD, median follow-up 2.2 years, reduction of the composite endpoint HR 0.85) confirm the benefit of further lowering in people with already established ASCVD, not "zero cholesterol as a target in a healthy twenty-year-old".
One more boundary. Triglycerides are associated with cardiovascular risk independently of LDL-C — this is the wording of the 2025 focused update, citing epidemiological work. But "associated" does not equal "lowering them with a statin-independent fibrate reduces ASCVD". PROMINENT (pemafibrate in 10 497 patients with type 2 diabetes, moderate hypertriglyceridaemia and low HDL-C) did not reduce MACE and increased ApoB and LDL-C. STRENGTH (an EPA+DHA mixture in 13 078 patients) did not reduce MACE. Therefore in this course LDL-C is the primary target; hypertriglyceridaemia is discussed separately and with different evidence.
The practical conclusion to take away from the lesson. When LDL-C is seen in a lipid profile, the question is not "is it normal relative to the laboratory reference" but "what is this person's risk category, and has the target set for that category been reached". A laboratory form marked "normal up to 3.0 mmol/L" is not a clinical target for a patient after myocardial infarction.