18.1 — Atherosclerosis

Autopsy studies of American soldiers killed in Korea, average age 22, found early atherosclerotic changes in around 77 percent of them.

The process starts in adolescence and takes decades to cause anything.

Which is the most important fact about it, and it cuts both ways: by the time symptoms appear, the disease has been developing for thirty years — and there are thirty years in which to change its course.

What it actually is

Not passive fat deposition in a pipe. It is a chronic inflammatory disease of the arterial wall (Chapter 16.3), and understanding it that way explains both the treatments and why some of them work better than lipid lowering alone would predict.

The sequence:

Endothelial dysfunction first. The lining of the artery stops producing enough nitric oxide (Chapter 7.5) and becomes more permeable and more adhesive. This is measurable years before any plaque exists, and it is caused by high LDL, smoking, high blood pressure, high glucose and inflammation.

LDL particles enter the wall and, once there, become oxidised.

And oxidised LDL is the trigger. The immune system recognises it as abnormal. Monocytes are recruited, enter the wall, become macrophages, and engulf it.

They cannot digest it. They fill with lipid and become foam cells — and the earliest visible lesion, the fatty streak, is a collection of them.

Smooth muscle cells migrate in and lay down collagen, forming a fibrous cap over a lipid-rich core.

And now the plaque behaves in one of two ways, and the difference is everything.

Stable and unstable plaques

A stable plaque has a thick fibrous cap and a small lipid core. It narrows the artery gradually, and the symptom is stable angina on exertion (Chapter 7.7).

An unstable plaque has a thin cap, a large lipid core, and a great deal of inflammation.

And here is the counter-intuitive part that changed cardiology.

Most heart attacks are caused by rupture of a plaque that was not severely narrowing the artery.

A plaque causing 80 percent narrowing produces angina and is usually stable. A plaque causing 30 percent narrowing may be inflamed, thin-capped, and about to rupture.

Which is why stenting a narrowing relieves angina and does not prevent heart attacks, and why drug treatment that stabilises plaques throughout the arterial tree does.

Rupture exposes the thrombogenic core to blood, a clot forms in seconds, and the artery occludes.

That is the mechanism of almost every heart attack and most ischaemic strokes.

Where it causes trouble

Coronary arteries — angina, heart attack (Chapters 7.7, 18.3).

Cerebral arteries — stroke (Chapter 18.6).

Peripheral arteries — intermittent claudication: cramping calf pain that comes on after a predictable walking distance and stops on resting (Chapter 6.7).

And a critical progression: pain at rest, particularly at night and relieved by hanging the leg down, means critical limb ischaemia (Chapter 14.4). That is a limb-threatening emergency, and it is frequently mistaken for cramp.

Renal arteries — hypertension and kidney failure.

Aorta — aneurysm and dissection (Chapter 7.5).

And the key point: it is one disease in different places. Someone with claudication has coronary disease until proven otherwise, and their leg symptoms are a marker of their overall risk more than a local problem.

The risk factors

Modifiable, and roughly in order of effect:

Smoking — and the effect is large. Doubles or triples cardiovascular risk, and it acts through endothelial damage, inflammation, increased clotting and lower HDL.

And stopping works fast. Excess coronary risk falls by around half within a year and approaches that of a non-smoker within 5 to 15 years.

LDL cholesterol — causal, established by Mendelian randomisation (Chapter 16.1). The relationship is continuous, with no threshold, and lifelong exposure matters more than a single measurement.

High blood pressure (Chapter 18.2).

Diabetes (Chapter 18.7).

Obesity, particularly visceral (Chapter 18.8).

Physical inactivity.

Poor diet.

Chronic kidney disease — an independent and under-recognised risk factor (Chapter 10.6).

Chronic inflammatory conditions — rheumatoid arthritis, psoriasis, lupus and HIV all raise cardiovascular risk beyond their conventional risk factors, which is direct evidence of the inflammatory mechanism.

Air pollution — the evidence has strengthened considerably, and fine particulate exposure is now recognised as a substantial contributor at population level.

Non-modifiable: age, male sex, family history, and ancestry — with South Asian populations at notably higher risk at lower body weights.

How risk is calculated

And this is worth understanding because it determines treatment.

Risk scores combine age, sex, smoking, blood pressure, cholesterol, diabetes and family history into a 10-year probability of a cardiovascular event.

Age dominates, which means a young person with terrible risk factors may score low and an older person with good ones may score high.

Which is why lifetime risk and "heart age" calculations are increasingly used alongside, particularly in younger people, where the 10-year figure is misleadingly reassuring.

Coronary artery calcium scoring — a low-dose CT counting calcified plaque. A score of zero is strongly reassuring; a high score substantially reclassifies risk upward, and it is increasingly used where the decision to treat is borderline.

Prevention

And this is the encouraging section, because the effect sizes are large.

The INTERHEART study examined heart attack patients across 52 countries and found that nine modifiable factors accounted for around 90 percent of the population attributable risk.

Smoking, cholesterol, blood pressure, diabetes, abdominal obesity, psychosocial factors, diet, alcohol and physical activity.

Which means the great majority of heart attacks are, in principle, preventable.

What to do, in order of effect:

Do not smoke. The single largest modifiable factor.

Move. 150 minutes a week of moderate activity reduces cardiovascular events by around 20 to 30 percent, and the largest gains are from moving from sedentary to a little rather than from a lot to more.

Diet. The Mediterranean pattern has the best evidence, from the PREDIMED trial — a randomised trial showing around a 30 percent reduction in major cardiovascular events. Not a supplement, not a single food: a pattern.

Control blood pressure.

Control diabetes.

Manage weight.

Sleep — both short and disrupted sleep are associated with increased risk, and sleep apnoea is a specific and treatable contributor (Chapter 8.5).

And chronic stress is a genuine risk factor rather than a soft one, acting through blood pressure, behaviour and inflammation.

Treatment

Statins — reduce LDL and stabilise plaques (Chapter 1.3).

And their benefit exceeds what the lipid reduction alone predicts, which is attributed to the anti-inflammatory effect.

Secondary prevention — after an event — has an NNT of around 20 to 40 over five years. Primary prevention in moderate-risk people is around 100. Same drug, different value (Chapter 16.1).

The muscle side effect question is covered in Chapter 6.7, and the short version is that blinded trials find muscle symptoms at almost the same rate on placebo.

Ezetimibe — blocks cholesterol absorption, used with or instead of statins.

PCSK9 inhibitors — injectable antibodies producing very large LDL reductions, for those at highest risk or intolerant of statins.

Aspirin — and the advice has changed. Clearly beneficial after an event. No longer routinely recommended for primary prevention in people without established disease, because the bleeding risk offsets the benefit in most.

Blood pressure treatment (Chapter 18.2).

Anti-inflammatory treatment — colchicine reduces cardiovascular events in established coronary disease, and it is cheap and old (Chapter 1.5). The CANTOS trial with an anti-inflammatory antibody established the principle (Chapter 16.3).

Revascularisation — stenting or bypass (Chapter 7.7), which relieves symptoms and, in specific high-risk anatomy, improves survival.

Can it be reversed?

Partially, and the honest answer is worth giving.

Plaque regression has been demonstrated on imaging with intensive lipid lowering — modest in size, and real.

Stabilisation is the larger effect, and it is what matters clinically: a plaque that does not rupture does not cause a heart attack whatever its size.

Lifestyle programmes have shown regression in small intensive trials, and the results are genuine and hard to sustain outside a trial.

The practical framing: you cannot undo thirty years quickly, and you can change what happens over the next thirty. Risk falls measurably within months of stopping smoking, controlling blood pressure and starting to move.

What the next page fixes

Chapter 18.2 covers the risk factor that affects more people than any other, produces no symptoms until it has caused damage, and is treatable with cheap tablets.