Lipoproteins as Risk Factors

Lipoproteins transport lipids through the aqueous blood environment. Their composition and behaviour determine cardiovascular risk. Low-density lipoprotein (LDL) is the primary atherogenic lipoprotein. It has high affinity for the arterial wall and is readily oxidised within the intima. Oxidised LDL promotes inflammation and thrombosis, initiating and propagating atherosclerotic plaque. LDL receptor mutations cause familial hypercholesterolaemia (FH), predisposing to premature cardiovascular disease.

Current interventions to reduce LDL include dietary modification, weight loss, exercise, and lipid-lowering drugs — particularly statins, which inhibit HMG-CoA reductase. In homozygous FH (no functional LDL receptors), MTP inhibitors (lomitapide) or apoB antisense therapy (mipomersen) reduce hepatic lipoprotein secretion, since VLDL assembly requires both MTP and apoB.

Lipoprotein(a) — Lp(a) — is produced exclusively in the liver and is strongly genetically determined. Its structure is ~80% homologous to plasminogen. Because it competes with plasminogen for fibrin binding, it prevents thrombus lysis and is thrombogenic. High Lp(a) (>50 mg/dL) in standard lipid panels is measured as LDL cholesterol, potentially mimicking FH. Statins do not lower Lp(a) and may increase it; PCSK9 inhibitors, Lp(a) apheresis, oestrogens, and niacin can reduce it.

High-density lipoprotein (HDL) is cardioprotective. Low HDL causes include genetic factors, liver disease, and secondary dyslipidaemias (familial combined hyperlipidaemia, type 2 diabetes, metabolic syndrome). Interventions: statins, fibrates, niacin, weight loss, exercise. Tangier disease (homozygous ABCA1 mutation) causes near-absent HDL, orange tonsils, peripheral neuropathy, and premature cardiovascular disease. Familial hypoalphalipoproteinaemia (heterozygous ABCA1) is more common and causes reduced HDL and premature heart disease.