Atherosclerosis and the biomarkers associated with it

Definition and burden. Atherosclerotic cardiovascular disease is the leading cause of death and disability in adults aged 75 and older. Atherosclerosis is a slow-developing chronic inflammatory disease that begins as early as the first decades of life, at the level of the intimal tunica of large-calibre arteries. The presence of atherosclerosis has been positively correlated with age at death even in ancient mummified populations, suggesting it is an inherent component of human ageing — but genetic and environmental factors modulate its severity and speed of progression, among which lipid disorders, in particular hypercholesterolaemia, are foremost.

Pathogenesis. The sequence is: endothelial injury and dysfunction (from shear stress at branch points, hypertension, smoking, hyperglycaemia, oxidised LDL) → increased permeability with subendothelial retention and oxidation of apoB-containing lipoproteins → monocyte adhesion and migration, differentiation into macrophages and uptake of oxidised LDL to form foam cells → fatty streak → smooth muscle migration and proliferation with fibrous cap formation → fibrofatty plaque with a necrotic lipid core → plaque rupture, fissuring, erosion or haemorrhage with superimposed thrombosis, producing the acute event. In ageing, cellular senescence primes the vessel and drives established disease forward, and "inflammageing" — chronically elevated inflammatory markers — contributes through inhibition of growth factors, increased catabolism and disturbed homeostatic signalling.

Risk factors. Non-modifiable: age (the strongest single predictor of cardiovascular risk), male sex, family history and genetic predisposition, ethnicity. Modifiable: dyslipidaemia, hypertension, diabetes mellitus, smoking, obesity and visceral adiposity, physical inactivity, chronic kidney disease. Emerging and geriatric-specific: frailty appears to be a cardiovascular risk factor unique to older people, sharing a pathogenetic link with ischaemic heart disease through chronic inflammation and haematological and endocrine factors; and loneliness, social isolation, depression and dementia are further risk factors that increase cardiovascular events in old age.

Established lipid biomarkers.

Inflammatory and other circulating biomarkers. High-sensitivity CRP — an established marker of residual inflammatory risk; a strong association exists between increasing age and increasing systemic inflammation as measured by CRP. Interleukin-6 — an upstream driver of the inflammatory pathway and a core marker of inflammageing and frailty. Lp-PLA2 and myeloperoxidase — markers of plaque inflammation and instability. Homocysteine — associated with risk, but lowering it with B vitamins does not reduce events. Fibrinogen and D-dimer — thrombotic risk. NT-proBNP and high-sensitivity troponin — markers of subclinical myocardial injury and strain that predict events in older adults, and are increasingly used as "newer biomarkers" of cardiovascular risk. Note that in older people a raised troponin and BNP frequently reflect chronic myocardial stress rather than acute events, so trends matter more than absolute values.

Imaging biomarkers and clinical use. Coronary artery calcium (CAC) score on non-contrast CT is the most useful risk-refining test — a score of zero confers a very low short-term risk and can justify withholding or deferring a statin, whereas a high score reclassifies the patient upward. Carotid intima-media thickness and carotid plaque on ultrasound, ankle brachial index and CT coronary angiography with plaque characterisation are alternatives. The practical role of all these markers is to refine risk when the decision to treat is uncertain — this matters especially in older adults, in whom standard risk calculators lose specificity because chronological age dominates the score. Management remains risk-factor modification: statin therapy to LDL targets, blood pressure and glycaemic control, smoking cessation, weight loss and exercise.

Two biomarkers have moved from research interest to guideline recommendation. First, Lipoprotein(a): ESC/EAS and 2025 AHA/ACC guidance now recommend measuring Lp(a) at least once in every adult's lifetime for risk stratification, and the first targeted therapies — pelacarsen (Lp(a)HORIZON), olpasiran and lepodisiran — are in phase 3 outcome trials, with pelacarsen lowering Lp(a) by around 80%. Second, residual inflammatory risk: pooled analyses of over 30,000 statin-treated patients (Ridker et al., Lancet 2023) showed that high-sensitivity CRP predicted future cardiovascular events and death more strongly than LDL-cholesterol did, supporting the dual-target concept — lower LDL for the lipid pathway and target inflammation with colchicine (LoDoCo2, COLCOT) for the inflammatory pathway. In parallel, the 2025 AHA/ACC hypertension guideline has adopted the PREVENT risk equations, which for the first time incorporate eGFR, urine albumin-creatinine ratio and HbA1c into routine cardiovascular risk estimation.