Atherosclerosis and cardiovascular risk assessment

• Atherosclerosis is the slow build-up of a fatty, fibrous plaque inside an artery wall. The plaque narrows the vessel, and if its cap tears, a clot forms that can block the artery and kill tissue downstream. ^[5]
• Coronary, cerebral and peripheral artery disease are not separate problems. They are the same process in different beds, and disease in one bed predicts disease in another.
• Atherosclerosis is silent for decades. The only way to prevent the first heart attack or stroke is to find the people who are heading toward it.
• That is what risk assessment does. It estimates 10-year (or 30-year) probability of a cardiovascular event from age, sex, blood pressure, lipids, smoking, diabetes, kidney function and other factors. ^[3]
• The newest tools are SCORE2 for European populations and PREVENT for United States adults, while the pooled cohort equations remain in wide use for deciding when to start a statin.

By the end of this page you should be able to:

1. Explain, step by step, how an atheroma forms, grows, becomes unstable and either ruptures or erodes.
2. Explain why plaques tend to rupture where arteries branch and why inflammation drives rupture.
3. Describe atherosclerosis as one systemic disease across the coronary, cerebral and peripheral beds and name the practical consequence (polyvascular disease).
4. Choose the right risk score for a patient and explain the trade-offs between SCORE2, PREVENT and the pooled cohort equations.
5. Apply the age-stratified SCORE2 categories and the PCE risk categories, and use risk-enhancing factors to reclassify an intermediate-risk patient.
6. Interpret a coronary artery calcium score and decide when it genuinely changes management.
7. Outline the lifestyle, risk-factor and low-resource management that follows from the estimated risk.

Atherosclerosis is the commonest cause of cardiovascular disease worldwide. According to the 2022 pathophysiology review by Jebari-Benslaiman and colleagues, cardiovascular disease is the leading cause of death globally, and atherosclerosis is its main driver. It sits behind coronary artery disease, ischaemic stroke and transient ischaemic attack, peripheral artery disease, mesenteric ischaemia and many cases of heart failure. The disease is common, it is largely silent until it produces an event, and the event is often fatal or disabling. Prevention is the treatment, and prevention requires risk assessment.

For a student meeting the topic for the first time, the central idea is not a list of risk factors but a single causal chain. A damaged endothelium lets LDL into the wall, the wall becomes inflamed, a plaque forms, the plaque's cap thins, the cap tears, a clot forms, and an organ downstream loses blood. Every risk factor in the next section exists only because it pushes one or more steps of that chain. Hold that chain in mind and the rest becomes reasoning rather than memorisation.

Atherosclerosis is the chronic, focal build-up of lipid-rich material, fibrous tissue and calcium within the wall of a large artery. The word comes from Greek for "gruel" (athero) and "hardening" (sclerosis), which is roughly what the plaque looks like in cross-section: a soft core of lipid and dead cells capped by hard fibrous tissue and, in older lesions, calcium.

Three structural stages are worth naming because they appear in every textbook and every board question:

• Fatty streak. The earliest lesion: a flat, lipid-rich streak of foam cells in the intima, visible even in children. It is reversible.
• Fibrous (atheromatous) plaque. A raised lesion with a lipid-rich necrotic core covered by a fibrous cap. This is the characteristic lesion of adult atherosclerosis.
• Complicated lesion. A plaque that has haemorrhaged, calcified, fissured or thrombosed. Complicated lesions are the ones that cause symptoms.

Atherosclerosis is classified mainly by the clinical bed it affects rather than by histology. A patient may have coronary artery disease (angina, myocardial infarction), cerebrovascular disease (transient ischaemic attack, ischaemic stroke), peripheral artery disease (claudication, critical limb ischaemia, non-healing ulcers), or polyvascular disease when two or more beds are involved. The pathogenesis review by Morrison and colleagues notes that polyvascular disease is common and is frequently under-recognised in daily practice.

According to the review by Morrison and colleagues, stroke causes roughly one in six deaths, the prevalence of coronary artery disease among adult Americans is estimated at about 7.1% (around 20 million people), and peripheral artery disease affects more than 236 million people worldwide. Collectively, atherosclerotic disease is the leading cause of death worldwide. The 2022 pathophysiology review by Jebari-Benslaiman and colleagues restates the same point: cardiovascular disease is the leading cause of mortality worldwide and atherosclerosis is its main driver. ^[6]

A few epidemiological features matter more than the headline numbers:

• The disease is age-driven but begins early. Fatty streaks are found in the coronary arteries of many young adults, while the clinical complications of atherosclerosis usually become apparent in middle age and later.
• Incidence fell in high-income countries from the 1970s onward as smoking, blood pressure and lipids were controlled, then plateaued and in some groups rose again with obesity and diabetes. In low- and middle-income countries incidence is still rising.
• The burden is strongly skewed by sex, ethnicity and geography, which is exactly why risk scores cannot be one-size-fits-all.

Nothing about atherosclerosis is a single cause. The 2018 AHA/ACC cholesterol guideline (executive summary, Grundy and colleagues) and the review by Morrison and colleagues list the same set of drivers, which can be grouped into modifiable and non-modifiable.

Non-modifiable. Age is the single strongest predictor; the arterial wall simply accumulates damage over time. Male sex, family history of premature atherosclerotic cardiovascular disease (men before 55, women before 65), and high-risk ancestry (for example South Asian) all add baseline risk independent of measured risk factors. ^[7]

Modifiable. Hypertension raises shear stress on the endothelium and makes it leaky. Smoking damages the endothelium and promotes thrombosis. LDL cholesterol is the substrate the plaque is built from. Diabetes accelerates every step through glycation and oxidation. Obesity drives dyslipidaemia, hypertension and insulin resistance. A poor diet (high in sodium, sugar and saturated fat) and inactivity amplify all of the above. Chronic kidney disease and inflammatory diseases (rheumatoid arthritis, psoriasis, HIV) add an inflammatory component that is not fully captured by the standard risk factors. Pregnancy-related conditions, specifically preeclampsia and premature menopause before age 40, identify women whose lifetime risk is higher than standard estimates suggest. ^[6][7]

The 2018 AHA/ACC guideline collects the less obvious markers under the heading risk-enhancing factors. They matter because they are the single most common way a borderline-risk patient is reclassified to a treatment candidate, and they are listed again in the risk-assessment section below.

This is the core of the topic. Read it as a timeline, not as a list.

Step 1. Endothelial dysfunction. The endothelium is a single-cell layer that lines every artery. In a healthy state it keeps blood cells and lipoproteins out of the wall and secretes vasodilating, anti-inflammatory and anti-clotting signals (nitric oxide above all). Blood flow patterns matter as much as chemistry here: at places where blood swirls rather than flows (branch points, bifurcations, outer walls of curves), shear stress on the endothelium is low and oscillatory. As Jebari-Benslaiman and colleagues explain, those regions are where plaques begin. Hypertension, smoking, diabetes and dyslipidaemia all damage the endothelium and reduce nitric oxide bioavailability.

Step 2. LDL retention and oxidation. Once the endothelium is leaky, LDL particles cross into the sub-endothelial space and become trapped. There they are oxidised. Oxidised LDL is not just a neutral fat; it is pro-inflammatory and pro-immunogenic and it drives almost everything that follows.

Step 3. Fatty streak. Oxidised LDL signals to the endothelium, which switches on adhesion molecules. Circulating monocytes stick, migrate into the wall and become macrophages. Those macrophages swallow oxidised LDL greedily and become foam cells. The accumulating foam cells make the fatty streak, the first visible lesion. Vascular smooth muscle cells from the media also migrate in and become foam cells, and in human coronary arteries smooth-muscle-derived foam cells make up at least half of them.

Step 4. Fibrous plaque. The now-established lesion triggers a repair response. Smooth muscle cells lay down a fibrous cap (collagen and elastin) over a growing lipid-rich necrotic core of dead foam cells, lipid debris and cholesterol crystals. The necrotic core and fibrous cap together are the hallmark of an advanced plaque. Cholesterol crystals within the core activate the NLRP3 inflammasome, driving production of IL-1beta and IL-18 and keeping the lesion inflamed for years.

Step 5. Plaque grows outward, then inward. Early plaques grow outward, so the lumen is preserved. Eventually the lesion bulges inward and narrows the lumen, producing progressive ischaemia (angina on exertion, claudication).

Step 6. Vulnerability and rupture. A plaque becomes dangerous not because it is large but because it is unstable. The vulnerable phenotype, described by Morrison and colleagues, has a thin fibrous cap, a large lipid-rich necrotic core, intraplaque haemorrhage and local inflammation. Two processes weaken the cap. First, inflammatory cytokines (IFN-gamma, IL-1beta, TNF-alpha) suppress collagen production and increase matrix metalloproteinases, which digest the collagen. Second, smooth muscle cells die, so new collagen is not replaced. Jebari-Benslaiman and colleagues emphasise that this inflammation is localised to the cap and shoulders of the plaque, which is why a plaque can be unstable without the whole patient being systemically inflamed.

Step 7. Rupture, erosion or haemorrhage. If the cap tears (rupture), the thrombogenic core meets the bloodstream and platelets and the coagulation cascade activate within minutes. The same can happen if the endothelium erodes away over a calcified or inflamed area (erosion), or if a new vessel inside the plaque bleeds and expands it. Thrombus usually grows acutely and either partially (unstable angina, TIA) or completely blocks the vessel (myocardial infarction, stroke, acute limb ischaemia).

Step 8. Aftermath. Some thrombi embolise distally and cause organ infarction. Most occlusive thrombi are eventually lysed and healing takes months, during which the plaque is covered by a new, thicker cap and becomes more fibrous. Repeated cycles of rupture and healing silently enlarge the plaque and account for its step-wise growth.

The clinical lesson to keep in mind: myocardial infarction and stroke usually come from rupture of a plaque that was not large enough to cause symptoms, not from a plaque that had been slowly choking the vessel. Slow narrowing causes angina and claudication; rupture causes sudden death and disablement. This is why finding and treating risk matters more than chasing symptoms.

Grossly, the arterial wall shows a spectrum from yellowish fatty streaks through white, raised fibrous plaques to hard calcified plaques. Histologically, the advanced plaque has a necrotic core containing cholesterol clefts, lipid debris and calcification, a cap of smooth muscle cells and collagen, an infiltrate of macrophages and lymphocytes at the shoulders, and microvessels running into the plaque from the vasa vasorum. That last feature explains intraplaque haemorrhage. Thrombus may be layered on top. Pathologists classify the major atherosclerotic lesions as fatty streak, intimal xanthoma, fibrous plaque, thin-cap fibroatheroma, plaque with erosion and ruptured plaque; from the bedside the distinction that matters is stable versus vulnerable, as in the table.

Atherosclerosis is silent for most of its course. The patient has no symptoms, the examination can be normal, and the first clue may be a catastrophe. Clinical features arise in one of three ways.

Progressive stenosis causes demand ischaemia: angina of effort and breathlessness in the coronary bed, claudication on a fixed distance in the lower limbs, mesenteric angina after meals, renal artery stenosis with resistant hypertension.

Rupture or erosion causes acute events: myocardial infarction, transient ischaemic attack and ischaemic stroke, acute limb ischaemia, and sudden death.

Constitutional features as clues. The disease does not itself produce fever or malaise, but the same risk factors produce others: an absent foot pulse, a carotid bruit, an aorto-iliac bruit, diminished ankle-brachial pressure, or poor wound healing.

Polyvascular disease deserves emphasis. A patient with established coronary disease has a high chance of concurrent carotid or peripheral disease; a patient presenting with claudication should be assumed to have coronary disease until it is excluded. The management section below returns to this point.

Because the disease is silent, differential diagnosis usually applies to an event or to an imaging finding, not to atherosclerosis itself. The main questions are:

• Is an acute coronary syndrome really atherosclerotic? Alternatives include coronary spasm, embolism, dissection, myocarditis, takotsubo and supply-demand mismatch in severe anaemia or sepsis. Electrocardiography, troponins and coronary imaging separate them.
• Is a transient focal neurological deficit a TIA? Migraine aura, seizure, hypoglycaemia, labyrinthine disorder and somatoform symptoms are the usual mimics.
• Is a painful, ischaemic limb atherosclerotic? Embolism from the heart or aorta, thrombosis of an aneurysm, vasculitis and hypercoagulable states all present similarly.
• Is a calcified plaque on imaging "atherosclerosis"? Medial calcification (Monckeberg) in diabetes and kidney disease is a separate process that does not narrow the lumen.

For the student the point is that risk markers and plaques are not the same thing. A high score means high probability, not disease, and a normal angiogram in a high-risk patient does not cancel the risk.

Investigations serve two separate purposes: measuring the risk (so that it can be lowered) and finding the disease that is already there.

Risk measurement. A minimal set that enables both SCORE2-type and PREVENT-type estimates: age, sex, smoking status, systolic and diastolic blood pressure, total and HDL cholesterol (to derive non-HDL cholesterol), fasting glucose or HbA1c, body mass index, estimated glomerular filtration rate from serum creatinine. Optional enhancers when clinically indicated: urine albumin-to-creatinine ratio, HbA1c in non-diabetic patients, licensed biomarkers (Lp(a), apoB, hsCRP), and the ankle-brachial index. Non-fasting lipids are acceptable because total and HDL cholesterol change little with fasting, and both PREVENT and SCORE2 work with non-HDL cholesterol. ^[3]

Finding disease that is already there. Resting ECG, echocardiography when heart failure or valve disease is suspected, Duplex ultrasound of carotids for a suspected bruit or after a TIA/stroke, ankle-brachial pressure for suspected claudication, and coronary artery calcium scanning. CAC scanning is the strongest single reclassification tool available to the generalist and is discussed in the next section.

Imaging note. Plaque itself can be visualised (carotid ultrasound, CT angiography, coronary CT), but imaging whole populations is neither necessary nor cost-effective. The standard approach is to estimate risk, treat the risk factors, and reserve imaging for symptomatic or high-risk individuals and for reclassification.

Atherosclerosis has no single diagnostic criterion; it is diagnosed by its consequences or by imaging. The closest thing to "staging" in routine practice is risk category, and that is where the scores live. Three scores dominate teaching and practice.

SCORE2 was developed by the SCORE2 working group and published in the European Heart Journal in 2021. It predicts 10-year risk of a first fatal or non-fatal cardiovascular event (myocardial infarction or stroke) in apparently healthy Europeans aged 40 to 69 years without diabetes, on the basis of age, sex, smoking status, systolic blood pressure and total and HDL cholesterol. SCORE2-OP is the parallel score for adults aged 70 and over. Headline facts from the development paper:

• Derived from 45 cohorts in 13 countries (677,684 people, 30,121 events) and externally validated in 25 cohorts in 15 countries (1,133,181 people, 43,492 events). C-indices in validation ranged from 0.67 to 0.81, which is moderate to good discrimination. ^[1]
• Recalibrated to four European regions defined by WHO age- and sex-standardised cardiovascular mortality per 100,000: low-risk region below 100, moderate-risk 100 to under 150, high-risk 150 to under 300, very high-risk 300 or more. A 50-year-old male smoker with blood pressure 140 mmHg, total cholesterol 5.5 mmol/L and HDL 1.3 mmol/L has an estimated 10-year risk of 5.9% in a low-risk country and 14.0% in a very high-risk country, which is why geography is built in. ^[1]
• It adjusts for the competing risk of non-cardiovascular death, which prevents over-estimation of benefit in older adults.
• It intentionally excludes diabetes and known cardiovascular disease because those groups are already high-risk.

The 2021 ESC risk review (Kim) published the age-stratified categories that translate a SCORE2 percentage into an action:

These age-stratified categories are those used in the 2021 ESC cardiovascular prevention guidance as summarised in the Kim review. The 2025 ESC/EAS focused update instead classifies absolute SCORE2 levels: below 2% low risk, 2% to below 10% moderate risk, 10% to below 20% high risk and 20% or more very high risk, with corresponding LDL-cholesterol thresholds of 1.8 mmol/L (70 mg/dL) or more in very high risk and 2.6 mmol/L (100 mg/dL) or more in high risk. ^{[2] [8]}

The keyword from the 2021 ESC guideline, captured in that review, is that no risk threshold is a mandate to treat. The decision is individual, taking lifetime risk, treatment benefit and harm, frailty, comorbidity and patient preference into account. A very high-risk score does not force a drug and a low score does not forbid one if other risk enhancers are present.

PREVENT, developed by Khan and colleagues and published in Circulation in 2023, is the newest United States score. It applies to adults aged 30 to 79 years without cardiovascular disease, and was built and validated on 6,612,004 adults. Its defining features: ^[3]

• Outcome. Total cardiovascular disease (atherosclerotic CVD plus heart failure), with separate equations for each subtype. This reflects the growing burden of heart failure as an outcome of cardiometabolic disease, something the older score did not capture.
• Predictors. Standard risk factors plus estimated glomerular filtration rate, with optional add-ons for urine albumin-to-creatinine ratio, HbA1c and social deprivation index. Race is deliberately not used as a biological predictor; the score is sex-specific and "race-free".
• Age as a time scale, which permits 10-year and 30-year risk estimates from the same model. Taking the life-course view is most valuable in younger adults, where a conventional 10-year risk looks reassuringly low while the lifetime risk is very high.
• Competing risk of non-cardiovascular death is accounted for.
• Validation performance was strong: median C-statistics for total CVD of 0.794 in women and 0.757 in men, with calibration slopes of 1.03 and 0.94. ^[3]

The pooled cohort equations (PCEs) were developed by Goff and colleagues and are the multivariable equations behind the 2013 and 2019 AHA/ACC primary prevention guidance. They estimate 10-year risk of a hard atherosclerotic event (myocardial infarction, death from coronary heart disease, or stroke) in adults aged 40 to 79. They are sex- and race-specific, with separate equations for Black and White adults only, and they require total and HDL cholesterol, blood pressure, diabetes status and smoking status. ^[3]

The PCEs divide 10-year ASCVD risk into four bands, as the 2018 cholesterol guideline sets out:

The bands and thresholds above are those of the 2018 AHA/ACC cholesterol guidance for the pooled cohort equations. The 2026 ACC/AHA dyslipidemia guideline, which now uses the PREVENT equations, sets a lower treatment threshold: pharmacological LDL-cholesterol lowering is recommended generally from a 3% or greater 10-year ASCVD risk, with moderate- to high-intensity statin therapy from 5% to below 10% and high-intensity therapy from 10% or more, while adults below 3% are managed with lifestyle measures and selected reclassification. This is a guideline-era difference in risk engines, not a correction of the pooled cohort bands. ^{[4] [9]}

Two honest caveats about the PCEs, both documented in the PREVENT development paper. First, the PCEs do not capture the total burden of disease, because heart failure is not an end point. Second, the slope of calibration for the PCEs was 0.50–0.54 for ASCVD, which corresponds to over-estimation of risk by roughly 50% in the contemporary populations studied. Newer American writers are increasingly using PREVENT rather than the PCEs, but the PCEs remain the score named in the 2019 guidance and in most American electronic health records. A further documented weakness, from the Korean risk-stratification review, is that pooled cohort equations perform poorly in older adults (75 and above), where the 10-year window is short relative to life expectancy and over-estimates risk because of competing non-cardiovascular mortality. ^[3]

A practical summary, with the geography of the patient as the first branch:

• European adult, aged 40 to 69, apparently healthy: SCORE2 (add SCORE2-OP over 70). Use the correct regional chart.
• United States adult, aged 30 to 79, apparently healthy: the PREVENT equations are the newest and most complete, especially when kidney disease or heart failure risk matters; the PCEs remain the reference in much existing guidance and many electronic records.
• Whichever score is used, the output is a probability, not a diagnosis. Treat the person, not the percentage.

The 2018 AHA/ACC cholesterol guideline lists the factors used in the clinician-patient discussion to decide whether a borderline or intermediate-risk patient should start a statin. None of these factors by itself obligates treatment, but a cluster of them moves a patient to a higher effective risk band, and the guideline notes that systemic inflammation in particular (chronic inflammatory disease, metabolic syndrome, renal disease, hsCRP 2.0 mg/L or more) justifies statin therapy in intermediate-risk patients.

When the decision is genuinely uncertain, the single most useful reclassification test is the CAC score (2018 AHA/ACC cholesterol guideline):

• A score of zero generally allows statin therapy to be withheld or delayed in an intermediate-risk patient, except in cigarette smokers, people with diabetes and those with a strong family history of premature atherosclerotic disease. ^[4]
• A score of 1 to 99 favours statin therapy, especially in those aged 55 or above. ^[4]
• A score of 100 Agatston units or more, or at the 75th percentile or above, indicates statin therapy unless the clinician-patient discussion leads elsewhere. ^[4]

CAC is an anatomical marker, so a zero score implies very little calcified plaque but not zero risk, and many plaques are lipid-rich and non-calcified.

Atherosclerosis is one disease. The 2023 review by Morrison and colleagues puts it bluntly: atherosclerosis may develop in any arterial segment and commonly produces disease in the coronary, carotid, cerebral, mesenteric, renal and lower-extremity beds. The inflammatory endothelial process is the same wherever it happens; the LDL, the monocytes, the foam cells and the fibrous cap are the same. What changes is the calibre of the vessel and the organ it feeds.

Schematically the pattern is this:

• Coronary arteries: stable angina, unstable angina, myocardial infarction, sudden death.
• Carotid and cerebral arteries: transient ischaemic attack, amaurosis fugax, cortical infarct, lacunar stroke (often small-vessel rather than atherothrombotic, but overlap is common).
• Peripheral (aorta, iliac, femoral): claudication, critical limb ischaemia, tissue loss, amputation.
• Others: mesenteric ischaemia, renal artery stenosis, aortic aneurysm.

Three consequences follow and should be remembered.

1. Risk is shared. A patient with one manifestation is assumed to have or to be developing disease in other beds until assessed. Cardiac events are the commonest cause of death in people with peripheral artery disease.
2. Risk factors are shared. There is no such thing as "coronary prevention" versus "stroke prevention"; lowering LDL, blood pressure and tobacco exposure lowers events in every bed, and the lipid pathway in particular is the shared root.
3. Polyvascular disease is under-recognised. Morrison's group identifies it as an increasingly recognised entity that increases the risk of future heart attack, stroke or death, and notes that clinicians often presume treatment does not vary by arterial distribution, which is a common source of under-treatment.

Management follows the risk estimate rather than the plaque image.

1. Lifestyle, for everyone. Heart-healthy diet, physical activity of at least 150 minutes a week of moderate intensity or 75 minutes of vigorous intensity, weight control, sodium intake below about 2 g a day, and tobacco cessation. Cessation is powerful: among heavy smokers it is associated with roughly a 40% reduction in cardiovascular risk within 5 years, but residual risk persists for up to 25 years, so earlier is much better. Referral to a structured cessation programme with pharmacotherapy triples quit rates. ^[6]

2. Lipid lowering for the high-risk majority. Statins are cornerstone therapy. High-intensity statins reduce LDL by 50% or more, moderate-intensity by 30 to 49%, low-intensity by under 30%, with typical high-intensity doses being atorvastatin 40–80 mg daily or rosuvastatin 20–40 mg daily. Targets: for patients with established atherosclerotic disease, a 50% reduction or an LDL of about 70 mg/dL (1.8 mmol/L) or less; for lower-risk primary prevention, lower LDL-C by at least 30%. If the target is not reached, add ezetimibe (further 13–20% reduction), and then a PCSK9 inhibitor. Newer small interfering RNA agents are in development; their place is not yet established in the guidelines cited here. Check local formularies, because dosing, availability and cost differ by health system. ^[4][6]

3. Blood pressure control. Each 20/10 mmHg rise above 115/75 mmHg roughly doubles the risk of death from stroke, heart disease and other vascular disease. Patients with established atherosclerotic disease should be treated to systolic blood pressure under 130 and diastolic under 80 mmHg, with first-line ACE inhibitors or ARBs, calcium-channel blockers or thiazide diuretics selected by patient profile. ^[6]

4. Glycaemic control. For most non-pregnant adults with diabetes, an HbA1c target of under 7% is appropriate, under 6.5% in younger patients and under 8% in those with limited life expectancy. Metformin is first-line pharmacotherapy; add SGLT2 inhibitors or GLP-1 receptor agonists for patients with established atherosclerosis because they reduce cardiovascular events. ^[6]

5. Antithrombotic therapy. For patients with established atherosclerotic disease, aspirin is the mainstay of secondary prevention. Dual antiplatelet therapy (aspirin plus a P2Y12 inhibitor) follows acute coronary syndrome, stroke or TIA, or revascularisation. In stable disease involving two or more vascular beds, aspirin plus low-dose rivaroxaban reduces cardiovascular events. These are management decisions for a clinical team, not for self-treatment.

6. Revascularisation. Angioplasty or bypass for flow-limiting coronary or lower-limb disease, carotid endarterectomy or stenting for symptomatic high-grade carotid stenosis. Revascularisation reduces symptoms and sometimes events; it does not remove the disease process, which is why medical therapy must continue.

Complications are the names of the events already listed: myocardial infarction, unstable angina, sudden cardiac death, ischaemic stroke and TIA, chronic coronary syndrome, heart failure from repeated infarction, peripheral ulcers and amputations, mesenteric ischaemia, renal impairment and hypertensive emergencies from renal artery stenosis, aortic aneurysm and dissection, and limb or organ loss from embolism. Polyvascular involvement multiplies these risks.

Prognosis depends on where the disease is and on how aggressively it is treated rather than on a score. In modern practice, after a first non-fatal event, long-term outlook has improved enormously: statins plus antiplatelet therapy and risk-factor control reduce recurrent events substantially compared with historical rates. The residual risk after maximal therapy is the current research frontier. Without treatment, once symptoms appear the outlook is poor and event rates are high. The most important message for a student is that the first event is often fatal or disabling, which is why prevention is the treatment.

Primary prevention is built on risk assessment, as described above. Secondary prevention means identifying established disease aggressively (lowering LDL further, tighter blood pressure, aspirin) and screening for polyvascular disease in anyone who has one manifestation (carotid ultrasound after stroke, Duplex leg arteries after claudication, cardiac history in claudication, peripheral pulses in everyone).

Screening whole populations with imaging is not supported by the evidence cited here: the standard strategy is to identify high-probability individuals with risk scores and treat risk factors. The 2018 AHA/ACC guidance supports selective screening for lipid disorders in children and adolescents: in those without cardiovascular risk factors or family history of early cardiovascular disease it may be reasonable to measure a lipid profile once between 9 and 11 years and again between 17 and 21 years, with earlier testing for familial hypercholesterolaemia when the family history warrants it, because half a lifetime of high LDL can be avoided by identifying familial hypercholesterolaemia early. ^[4]

Children and adolescents. Acquired atherosclerosis begins in childhood. Fatty streaks are found in young adults. Screening LDL in childhood detects familial hypercholesterolaemia, in which statin treatment is lifelong. Diet and activity are the interventions at this age. ^[4]

Pregnancy. Pregnancy is a cardiovascular stress test: preeclampsia and gestational hypertension identify women with excess long-term cardiovascular risk. Post-partum counselling should include lifestyle advice, blood pressure follow-up and early re-checking of lipids.

Women around menopause. Premature menopause before 40 is a risk enhancer; after menopause general risk rises toward male levels over the following decade. Framingham-type scores can under-estimate lifetime risk in young women because their 10-year risk stays low until they are older.

Older adults. The 2021 ESC risk review and the 2018 guideline both treat decisions as individual. Pooled cohort equations over-estimate risk over 70 because of competing mortality; PREVENT handles competing risk better. Treatment benefit must be weighed against life expectancy, frailty and polypharmacy. There is strong evidence for treating adults over 75 with established disease; in primary prevention the evidence is thinner and shared decision is essential.

Ethnicity. South Asian patients carry excess risk at the same measured risk factors; black patients carry excess hypertension and stroke risk; Hispanic/Latino is a heterogeneous label that should be unpacked (ancestry, socioeconomic status, acculturation). The 2018 guideline covers this in detail. PREVENT addresses some of the ancestry problem by being race-free and by using social deprivation and kidney function as variables.

Chronic kidney disease and diabetes. Both automatically put a patient into a high-risk band for management purposes. PREVENT explicitly includes eGFR and optional UACR and HbA1c.

Most atherosclerosis occurs in, or will occur in, low- and middle-income countries, and the tools in this article must be used within the resources available.

• Core measurements are cheap and non-fasting: blood pressure, body mass index, a random glucose (or fasting glucose), non-fasting total and HDL cholesterol. Non-fasting lipids are practical and valid for estimating risk.
• Present the score as a guide and not a gate. The 2021 ESC guidance itself states that no risk threshold mandates treatment.
• Generic statins are inexpensive and on the WHO essential medicines list; high-intensity regimens exist.
• CAC scanning will not be available; ultrasound (carotid, ABI) is cheaper and can refine risk when doubt remains.
• Tobacco is the single most cost-effective target. Where clinics have a nurse or pharmacist, brief advice plus combination nicotine therapy outperforms unsupported advice.
• Where referral systems exist, identify polyvascular disease and refer for single-visit assessment; where they do not, assume multi-bed disease and treat the shared risk factors.
• Where laboratory testing is limited, treat visually identifiable very-high-risk patients (diabetes with complications, hypertension with established target-organ damage, symptomatic PAD or TIA) with moderate-intensity statin and blood pressure control without waiting for a calculated score.

• Atherosclerosis is the accumulation of lipid-rich plaque in large arteries. Its complications are myocardial infarction, ischaemic stroke and peripheral artery disease.
• The vulnerable plaque has a thin fibrous cap, a large lipid-rich necrotic core and local inflammation, and it tends to rupture at branch points.
• Rupture, not stenosis, causes infarction: most acute events come from plaques that were not haemodynamically significant.
• Coronary, cerebral and peripheral disease are one disease process in different beds; polyvascular disease is under-recognised.
• Risk scores are probabilities, not diagnoses. SCORE2 (European, ages 40–69, fatal plus non-fatal events, four regions) and PREVENT (US, ages 30–79, total CVD including heart failure, race-free, eGFR included) are the newest; pooled cohort equations remain in wide use.
• SCORE2 risk categories are age-stratified under the 2021 ESC guidance: under 50, under 2.5% low-moderate, 2.5 to under 7.5% high, 7.5% or more very high; 50 to 69, the same bands at under 5%, 5 to under 10%, 10% or more; 70 and over under 7.5%, 7.5 to under 15%, 15% or more. The 2025 ESC/EAS focused update instead uses absolute SCORE2 levels: below 2% low, 2 to below 10% moderate, 10 to below 20% high, 20% or more very high. ^{[2] [8]}
• PCE risk bands are low under 5%, borderline 5 to under 7.5%, intermediate 7.5 to under 20%, high 20% or more, and they over-estimate contemporary risk by roughly half. ^[7]
• No threshold mandates treatment. Risk-enhancing factors (family history, Lp(a), apoB, hsCRP, CKD, ABI under 0.9, South Asian ancestry, preeclampsia, premature menopause, inflammatory disease) reclassify borderline and intermediate patients.
• Coronary artery calcium is the single best reclassifier: zero allows delay in most patients, 1 to 99 favours statin, 100 or more indicates it.
• High-intensity statins reduce LDL by at least 50%; treatment targets are under about 1.8 mmol/L (70 mg/dL) for established disease.
• For most non-pregnant adults with diabetes, an HbA1c target under 7% applies; metformin first, then SGLT2 inhibitors or GLP-1 receptor agonists when atherosclerosis is present.
• Tobacco cessation gives roughly a 40% cardiovascular risk reduction within 5 years in heavy smokers.
• The lowest-cost prevention strategy in any setting is risk-factor treatment, and treatment should not wait for a calculated score when the clinical risk is obvious.

Coronary artery disease and myocardial infarction; ischaemic stroke and transient ischaemic attack; peripheral artery disease; familial hypercholesterolaemia; hypertension; diabetes mellitus and atherosclerosis; chronic kidney disease and cardiovascular risk; smoking cessation; statin therapy; cardiac physical examination; ECG interpretation; cardiac imaging.