Describe the biochemical basis of atherosclerosis and the lipid risk factors.

Definition

Biochemical Pathogenesis

Endothelial injury — hypertension, smoking, hyperglycaemia, turbulent flow → LDL enters the intima and is retained by proteoglycans → oxidation of LDL — the key step → Oxidised LDL taken up by macrophages via scavenger receptors → Scavenger receptors are not down-regulated by cholesterol → foam cells → fatty streak → Smooth muscle migration, collagen → fibrous plaque → Plaque rupture → thrombosis → infarction

• The crucial point is that the scavenger receptor has no feedback control — the macrophage keeps engulfing oxidised LDL until it becomes a foam cell

Lipid Risk Factors

Non-lipid Contributors

• Homocysteine — damages endothelium; raised in folate, B6 and B12 deficiency
• Diabetes — glycation of LDL makes it more atherogenic and less well cleared
• Smoking — oxidative stress, endothelial injury, ↓ HDL
• Hypertension — mechanical injury and increased LDL entry
• Inflammation — hs-CRP is a marker of risk
• Small dense LDL is far more atherogenic than large buoyant LDL

WHY HDL Is Protective

• Reverse cholesterol transport — the only route by which peripheral cholesterol reaches the liver for excretion
• Antioxidant — carries paraoxonase, which prevents LDL oxidation
• Anti-inflammatory and antithrombotic
• Raised by exercise, moderate alcohol, oestrogen and stopping smoking

Applied Aspects

• Statins are the mainstay — they lower LDL and also stabilise the plaque, an effect partly independent of cholesterol lowering
• Ezetimibe blocks intestinal absorption; PCSK9 inhibitors prevent degradation of the LDL receptor, giving very large reductions
• Antioxidant vitamins have failed in trials despite the oxidation hypothesis — a reminder that a plausible mechanism does not guarantee benefit
• Indians develop coronary disease a decade earlier and at lower LDL levels than Western populations, with a characteristic pattern of low HDL, high triglyceride and raised Lp(a)