In symptomatic individuals, elevated low-density lipoprotein cholesterol (LDL-C) is associated with a higher risk of non-calcified plaque and future coronary heart disease (CHD) events, even with a coronary artery calcification (CAC) score of zero, a finding most pronounced in younger adults.¹

This challenges the perception of a zero CAC score as a universally low-risk marker, particularly over a long-term horizon.

This cohort study analysed data from 23,777 symptomatic individuals in the Western Denmark Heart Registry who underwent coronary computed tomography angiography (CCTA) between 2008 and 2021 and had a CAC score of zero.¹ The median age of the cohort was 54 years, 61% were women, and the median follow-up was 7.1 years.

Outcomes assessed were the presence of non-calcified plaque on CCTA and the incidence of CHD events, defined as myocardial infarction or late coronary revascularisation (≥90 days after CCTA).

The overall prevalence of non-calcified plaques was 11%. A direct association was found between LDL-C levels and the presence of these plaques. For each 1 mmol/L increase in LDL-C, the adjusted odds ratio (aOR) for having non-calcified plaques was 1.21. This association was strongest in individuals aged ≤45 years (aOR 1.39), compared to those aged 46–60 (aOR 1.22) and >60 (aOR 1.11).

During follow-up, 299 CHD events occurred (1.3% of the cohort). Higher LDL-C was also associated with a greater risk of future CHD events. The overall adjusted hazard ratio (aHR) was 1.28 for each 1 mmol/L increase in LDL-C. Again, the relative risk was most pronounced in the youngest age group (≤45 years), with an aHR of 1.37.

The findings indicate that in symptomatic patients, a CAC score of zero does not negate the risk posed by elevated LDL-C. The strong association between LDL-C, non-calcified plaque, and future CHD events, particularly in younger individuals, suggests that atherosclerosis is actively developing despite the absence of calcification.

These results underscore the importance of managing LDL-C over a long-term perspective, even when a CAC score is zero. For younger patients, who have a long remaining life expectancy, a zero CAC score may not provide the same level of reassurance as it does for older individuals. Early management of dyslipidaemia remains a crucial component of long-term CHD prevention.

This study was funded by the Danish Cardiovascular Academy, the Danish Heart Foundation, and the Novo Nordisk Foundation.

References

1. Andersen MH, Jensen JM, Kanstrup H, et al. Low-density lipoprotein cholesterol and cardiovascular risk in the absence of calcifications on computed tomography: the Western Denmark Heart Registry. Eur Heart J. 2025;46(46):5062–5072. https://doi.org/10.1093/eurheartj/ehaf497

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