A multicohort study published in the Journal of the American College of Cardiology has shown that elevated lipoprotein(a) is linked to a higher 15-year risk of atherosclerotic cardiovascular disease (ASCVD), independent of coronary artery calcium (CAC) scores, although individuals with a CAC score of zero continue to exhibit relatively low overall event rates even when Lp(a) levels are high. Drawing on data from more than 11,000 participants, this large analysis highlights that both lipoprotein(a) [Lp(a)] and CAC act as independent yet complementary predictors of cardiovascular risk, helping to resolve uncertainty of the usefulness of CAC scoring in individuals with elevated Lp(a), a lipid particle often associated with noncalcified plaque.
Lipoprotein(a), a genetically determined lipid particle, has increasingly been recognized as an important contributor to cardiovascular risk, particularly because of its pro-atherogenic, pro-inflammatory, and pro-thrombotic properties. Structurally similar to LDL cholesterol but containing an additional apolipoprotein(a) component, Lp(a) can promote plaque formation, impair fibrinolysis, and accelerate vascular inflammation. Global estimates suggest that nearly 20–25% of the population has elevated Lp(a) levels, making it one of the most common inherited lipid abnormalities.
Despite its importance, Lp(a) has remained underutilized in routine clinical practice, partly due to limited awareness and the historical lack of targeted therapies. Current guidelines from organizations such as the American College of Cardiology and the European Society of Cardiology increasingly recommend at least one lifetime measurement of Lp(a), especially in individuals with a family history of premature cardiovascular disease or unexplained high risk.
Coronary artery calcium scoring, obtained through noninvasive CT imaging, remains a cornerstone of modern risk stratification. A CAC score of zero is often referred to as a “power of zero,” reflecting its strong negative predictive value for near-term cardiovascular events. However, CAC reflects accumulated calcified plaque burden and may not fully capture earlier or noncalcified disease, which is where Lp(a) may play a more prominent role.
The study findings help resolve this clinical uncertainty by demonstrating that both Lp(a) and CAC act as independent and complementary predictors of cardiovascular risk. Individuals with Lp(a) levels above 50 mg/dL had a 24% higher risk of ASCVD, while the presence of any coronary artery calcium more than doubled the risk. Importantly, no significant interaction was observed between the two markers, indicating that each contributes additively rather than modifying the effect of the other. This additive effect suggests that combining the two measures can refine risk prediction beyond what either marker can achieve alone.
Even among individuals with a CAC score of zero, typically considered a low-risk group, those with elevated Lp(a) showed slightly higher event rates compared to those with lower levels. However, the absolute risk in this subgroup remained low, reinforcing the clinical value of a zero CAC score as a reassuring finding. In contrast, risk increased substantially in individuals with detectable calcium, particularly at higher levels. Participants with both CAC scores of 300 or greater and elevated Lp(a) faced the highest risk, with more than a sixfold increase in cardiovascular events, highlighting a subgroup that may benefit from more aggressive preventive strategies.
The observed patterns were consistent across age and sex groups, although absolute risk was higher among men and individuals over 50 years of age. These findings align with known epidemiological trends in cardiovascular disease and support the broad applicability of the results. Notably, the study also adjusted for traditional risk factors such as hypertension, diabetes, smoking, and LDL cholesterol, underscoring that Lp(a) contributes additional risk beyond established predictors.
Experts say the results have immediate clinical relevance. In practice, individuals with elevated Lp(a) but a CAC score of zero may still be managed conservatively with lifestyle optimization and standard preventive care, while those with both elevated Lp(a) and high CAC may warrant more intensive interventions, including aggressive lipid lowering and closer monitoring. The findings also support the growing use of CAC scoring to guide statin therapy decisions in borderline- or intermediate-risk patients.
The study arrives at a time of rapid progress in Lp(a)-targeted therapeutics. Novel agents such as antisense oligonucleotides and small interfering RNA (siRNA) therapies, currently in advanced clinical trials, have shown the ability to reduce Lp(a) levels by up to 80–90%, raising hopes for more precise and personalized cardiovascular prevention in the near future.
The findings reinforce a more nuanced approach to cardiovascular risk evaluation, emphasizing that while a CAC score of zero is reassuring, it does not completely eliminate risk in individuals with elevated lipoprotein(a). By integrating genetic risk markers like Lp(a) with imaging tools such as CAC scoring, clinicians may be better equipped to identify high-risk individuals earlier and tailor preventive strategies more effectively, marking an important step toward more personalized cardiovascular care.
References
- Bhatia, H, Fan, Y, Dharmavaram, G. et al. Use of Coronary Artery Calcium Scoring in Individuals With Elevated Lipoprotein(a): A Multicohort Study. JACC. Null2026.