Determinants of incident CHD in individuals without traditional CV risk factors (CVRFs) remain poorly understood.

Elevated triglycerides and hsCRP were significantly associated with an increased CHD risk even in CVRF-free individuals.

Biomarker-based assessment reveals residual CHD risk in individuals, deemed metabolically healthy by conventional standards.

The major predictors of future coronary heart disease (CHD) events in individuals without traditional modifiable cardiovascular risk factors (CVRFs) remain unknown. We investigated the association between circulating biomarkers, reflecting residual risk, with incident CHD in a general population, according to the presence of five CVRFs (hypertension, diabetes mellitus, hypercholesterolemia, smoking and obesity) at baseline.

Overall 212,598 CHD-free individuals from 21 European population-based cohorts were stratified by CVRF burden into three groups, having zero (n = 35,707), one (n = 68,548) or ≥2 (n = 108,343) risk factors at baseline. Five biomarkers (triglycerides (TGs), high-sensitivity C-reactive protein (hsCRP), cystatin C, N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I) were assessed in a subset with available measurements.

During a median follow-up of 13.97 years, 17,499 participants developed incident CHD with 453 events occurring among individuals without CVRFs. Although increased concentrations of all biomarkers were related to incident CHD, significant risk modulation by CVRFs was seen only for TGs and, to a lesser extent, for hsCRP. The fully-adjusted sub-distribution Hazard Ratios (95 % CI) were for TGs (≥vs < 1.70 mmol/L) 1.66 (1.29–2.15) in those without CVRFs versus 1.35 (1.21–1.49)/1.14 (1.07–1.20) in those with 1 or ≥2 risk factors (pinteraction<0.01) and for hsCRP (≥vs < 2 mg/L) 1.39 (1.02–1.90) versus 1.42 (1.26–1.61) or 1.22 (1.13–1.32), respectively (pinteraction = 0.092).

Even in the absence of CVRFs, elevated triglycerides and hsCRP were significantly associated with an increased risk of CHD. These results highlight the importance of residual risk assessment using those biomarkers in individuals deemed metabolically healthy by conventional standards.

Cardiovascular risk factors (CVRFs)

Coronary heart disease

General population

Circulating biomarkers

Triglycerides

High-sensitivity C-Reactive protein (hsCRP)

© 2025 The Authors. Published by Elsevier B.V.