Highlights
1. In symptomatic individuals with a coronary artery calcium (CAC) score of zero, 11% were found to have non-calcified plaques upon coronary computed tomography angiography (CCTA).
2. Each 1 mmol/L increase in LDL-C was associated with a 21% higher risk of non-calcified plaque and a 28% higher risk of coronary heart disease (CHD) events.
3. The association between LDL-C and cardiovascular risk was most pronounced in younger patients (age ≤45), suggesting that LDL-C control is critical even when calcification is absent.
Background: The Clinical Utility and Limitations of the CAC Score
In contemporary cardiovascular medicine, the coronary artery calcium (CAC) score has emerged as a powerful tool for risk stratification. A CAC score of zero is often interpreted as a sign of very low cardiovascular risk, frequently referred to as the “power of zero.” In many clinical guidelines, a score of zero provides a “warranty period” during which the initiation of statin therapy may be safely deferred in asymptomatic individuals. However, the biological reality of atherosclerosis is more complex. Atherosclerotic plaque progression begins with lipid accumulation and non-calcified (soft) plaque formation; calcification is a later stage of the disease process. This raises a critical clinical question: Does a CAC score of zero truly signify the absence of risk in symptomatic patients, or does it merely reflect the absence of advanced, calcified disease?
The reliance on CAC scoring alone may be particularly problematic in younger populations. Because calcification takes years to develop, younger individuals with high LDL-C may harbor significant burdens of non-calcified plaque that are invisible to traditional calcium scoring but detectable via coronary computed tomography angiography (CCTA). This study, utilizing data from the Western Denmark Heart Registry, sought to investigate the relationship between low-density lipoprotein cholesterol (LDL-C) levels, the presence of non-calcified plaque, and long-term cardiovascular outcomes in individuals with a CAC score of zero.
Study Design and Methodology
Patient Population and Selection
This large-scale cohort study utilized the Western Denmark Heart Registry, a comprehensive clinical database. The researchers included 23,777 symptomatic individuals who underwent CCTA between 2008 and 2021 and were found to have a CAC score of zero at the time of imaging. The median age of the cohort was 54 years, with a notable representation of younger individuals (25% aged 47 or younger) and a female majority (61%). Symptomatic status was defined by the presence of chest pain or dyspnea, which prompted the clinical referral for cardiac imaging.
Outcome Measures
The study focused on two primary outcomes. First, the presence of non-calcified plaque was assessed using CCTA, which allows for the visualization of the vessel lumen and the detection of non-calcified atherosclerotic components. Second, the study tracked coronary heart disease (CHD) events over a median follow-up period of 7.1 years. CHD events were defined as a composite of myocardial infarction and coronary revascularization. The researchers calculated adjusted odds ratios (aOR) for the presence of plaque and adjusted hazard ratios (aHR) for CHD events, controlling for traditional risk factors such as hypertension, smoking status, diabetes, and age.
Key Findings: The Hidden Burden of Non-Calcified Plaque
LDL-C and Plaque Prevalence
Despite having a calcium score of zero, 11% of the study population (2,604 individuals) had evidence of non-calcified plaque on CCTA. The analysis revealed a clear dose-response relationship between LDL-C levels and the presence of these plaques. For every 1 mmol/L (approximately 38.7 mg/dL) increase in LDL-C, the overall adjusted odds ratio for having non-calcified plaque was 1.21 (95% CI 1.16–1.27). This indicates that even in the absence of calcification, LDL-C remains a primary driver of structural vascular disease.
Predicting Future Coronary Heart Disease Events
During the follow-up period, 299 CHD events occurred. While the absolute event rate was relatively low (around 1%), the relative risk associated with LDL-C was significant. Each 1 mmol/L increase in LDL-C was associated with a 28% increase in the risk of a future CHD event (aHR 1.28; 95% CI 1.13–1.46). This finding underscores that LDL-C continues to exert a pathogenic effect on the vasculature even when the calcium score is zero, likely through the progression of these non-calcified lesions into unstable plaques or obstructive disease.
Age-Specific Risks: The Vulnerability of the Young
One of the most striking aspects of the study was the age-stratified analysis. The association between LDL-C and both plaque presence and CHD events was strongest in the youngest age group (≤45 years). For these younger individuals, the aOR for non-calcified plaque per 1 mmol/L increase in LDL-C was 1.39 (95% CI 1.23–1.56), and the aHR for CHD events was 1.37 (95% CI 1.04–1.82).
In contrast, while the associations remained statistically significant for individuals aged 46–60 and those over 60, the magnitude of the effect was smaller. This suggests that in younger patients, a CAC score of zero is less reliable as a marker of low risk if LDL-C is significantly elevated. In these patients, the “warranty” of a zero calcium score may be shorter, as they are at an earlier stage of the atherosclerotic continuum where plaques are exclusively non-calcified.
Expert Commentary: Re-evaluating the ‘Warranty’ of CAC = 0
The findings from the Western Denmark Heart Registry challenge the increasingly common practice of using a CAC score of zero to justify the avoidance of statin therapy in symptomatic patients. While a CAC score of zero is indeed a favorable prognostic sign, it does not represent a biological “clean bill of health” regarding atherosclerosis. The presence of non-calcified plaque in 11% of this cohort demonstrates that a significant minority of symptomatic patients with zero calcium still have coronary artery disease.
The Importance of Early Intervention in Younger Patients
The heightened risk observed in younger patients highlights the concept of “cumulative LDL-C exposure” or “cholesterol years.” Atherosclerosis is a lifelong process. A young person with high LDL-C and a CAC of zero may be in the early, inflammatory phase of plaque development. If clinicians wait for the calcium score to become positive before initiating therapy, they may miss the optimal window for primary prevention. By the time calcium is detectable, the atherosclerotic burden is already well-established. This study suggests that for younger symptomatic patients, LDL-C levels should perhaps carry more weight in the decision-making process than the calcium score alone.
Study Limitations and Considerations
It is important to note that this study focused on symptomatic individuals. The prevalence of non-calcified plaque and the rate of CHD events might be lower in an asymptomatic screening population. Furthermore, while the relative risk associated with LDL-C was high, the absolute risk of events over seven years in the CAC=0 group remained low. Clinicians must balance these relative and absolute risks when discussing treatment options with patients. Additionally, CCTA is a more invasive and resource-intensive procedure than simple CAC scoring, and its routine use for all patients with a CAC of zero is not currently supported by all guidelines.
Conclusion
The Western Denmark Heart Registry study provides robust evidence that LDL-C is a significant risk factor for cardiovascular disease even in the absence of coronary calcification. The “power of zero” should be interpreted with caution, particularly in symptomatic patients and those under the age of 45. In these populations, elevated LDL-C is a strong predictor of non-calcified plaque and future coronary events. These findings reinforce the importance of long-term LDL-C management as a cornerstone of cardiovascular prevention, regardless of the initial calcium score. For the clinician, this means that a CAC score of zero should be viewed as one piece of the diagnostic puzzle, not a definitive reason to ignore elevated LDL-C levels.
References
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. doi:10.1093/eurheartj/ehaf497.
