Elevated LDL-c is causal of atherosclerosis

Several lines of evidence together strongly suggest that LDL-c is causal in the development of atherosclerotic disease.

• Studies in animal models have demonstrated that atherosclerosis can be induced by increasing LDL-c via diet or genetic modification.
• Epidemiological studies have identified LDL-c levels as risk factors for myocardial infarction.
• Indeed, the elevated LDL-c level is the main factor in patients with familial hypercholesterolemia (FH) that is related to the premature CV events.
• Genetic Mendelian randomization studies also point into the direction of LDL-c being causal in atherogenesis, since genetic variants associated with lower LDL-c levels are associated with lower CV risk, and genetic variants that are linked to elevated LDL-c levels, associate with higher risk.
• Genetic variations in the PCSK9 gene further corroborate this: in carriers of PCSK9 loss-of-function (LOF) mutations, LDL-c levels are very low and these individuals are largely protected from CV events, while those with PCSK9 gain-of-function mutations show elevated LDL-c levels and increased CV risk. LOF mutations in the LDL receptor (LDLR) gene or the Apolipoprotein B (APOB) gene are also associated with elevated LDL-c levels and a common cause of FH.
• Randomized controlled trial evidence on LDL-c lowering treatment with statins, cholesterol absorption inhibition and PCSK9 inhibition show an association with reduction of CV events and can induce plaque regression.
• Statins remodel coronary plaque composition and favor plaque stabilization.

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References