High Lipoprotein(a) in Cardiovascular Disease

Corresponding Author

High lipoprotein(a), present in 1 in 5 individuals, is a genetically determined, causal, but often overlooked, risk factor for atherosclerotic cardiovascular disease (ASCVD).¹ Although large-scale routine clinical measurement is possible, implementing this in clinical practice lags behind both the evidence and most guideline recommendations.² In the 2025 update of the European Society of Cardiology/European Atherosclerosis Society dyslipidemia guidelines, measurement is recommended in all, and lipoprotein(a) levels >50 mg/dL (≈105 nmol/L) are now considered a cardiovascular risk-enhancing factor, justifying possible intensification of treatment.³ Likewise, the recently published 2026 American College of Cardiology/American Heart Association dyslipidemia guidelines now recommend lipoprotein(a) measurement at least once in all adults.⁴ At the same time, the Lp(a)HORIZON trial (NCT04023552), the first of four phase 3 cardiovascular outcome trials of highly potent lipoprotein(a)-lowering therapies, is expected to complete in 2026.⁵ Presently, the most pressing clinical challenge is the current very low lipoprotein(a) testing rates; we should not wait for lipoprotein(a)-lowering therapies, but rather start measuring now.⁶ Measurement is meaningful because it allows for personalized and more accurate risk estimation, supporting shared decision-making and earlier and more intensive treatment of conventional modifiable risk factors in individuals with high lipoprotein(a).¹

Thus, despite most guidelines now recommending testing in all,⁷ testing rates remain strikingly low. Recent data from the U.S. and Europe show that <1% of the general population have ever been tested.^8,9 This is even more concerning when we consider the fact that lipoprotein(a) concentrations are not evenly distributed: levels are, on average, four times higher in Black individuals and are also higher in postmenopausal women vs men of similar age.^10,11 Notably, the cardiovascular risk appears to increase continuously across the spectrum of lipoprotein(a) concentrations regardless of sex or ethnicity.¹ Accordingly, failure to measure lipoprotein(a) may led to systematic underestimation of the lifetime cardiovascular risk in groups already vulnerable to underrepresentation in diagnosis and treatment.

In this issue of JACC: Case Reports, Bawahab and Vasile¹² present a clear example of this clinical problem. They describe a 35-year-old African American woman with recurrent chest pain, minimal traditional cardiovascular risk factors, and severe multivessel coronary artery disease. Her conventional lipid profile did not immediately suggest an extreme-risk phenotype, with a low-density lipoprotein cholesterol (LDL-C) of 62 mg/dL (1.6 mmol/L) and triglycerides of 63 mg/dL (0.7 mmol/L); however, her high-sensitivity C-reactive protein (hsCRP) was 11.2 mg/L and her lipoprotein(a) was 60 mg/dL (∼127 nmol/L). She underwent percutaneous coronary intervention and was subsequently treated with intensive secondary prevention, including rosuvastatin and evolocumab, achieving an LDL-C <15 mg/dL (0.39 mmol/L). Nonetheless, within 6 months, she developed recurrent angina, and progression of disease with in-stent restenosis. At follow-up, both lipoprotein(a) and hsCRP remained high at 151 nmol/L (∼67.5 mg/dL) and 3.7 mg/L, respectively.

The paper has several strengths. Most importantly, it provides a clinically clear, well-documented illustration of premature and progressive coronary disease in a young Black woman whose risk may have been underestimated by standard risk calculators. It also highlights a phenotype that is highly relevant to preventive cardiology: severe ASCVD but a relatively normal lipid profile, few conventional risk factors, and substantial LDL-C lowering, yet persistent residual risk. In addition, the case is notable because it concerns a young Black woman, a group in whom average lipoprotein(a) levels are higher, yet in whom testing rates are particularly low.^9,10 The report therefore is not only an interesting case, but also a reminder that lipoprotein(a)-associated risk cannot be deduced from markedly elevated LDL-C or other conventional risk profiles that clinicians may associate with early coronary disease. Lipoprotein(a) must be measured.

What, then, does this case add to the literature? First, it reinforces the concept that high lipoprotein(a) may be particularly important in patients with premature, disproportionate, or otherwise unexplained coronary disease. Second, it highlights that residual risk may persist even after treatment of conventional risk factors, and that lipoprotein(a) may be one contributor to continued disease progression even when LDL-C has been reduced to very low levels. Third, it supports the clear argument that lipoprotein(a) should be measured early, ideally as part of the first lipid profile, rather than after a major clinical event. The usefulness of such a measurement is not only in identifying patients who may become eligible for future lipoprotein(a)-lowering therapies, but also in improving current care through more precise risk communication, more intensive lipid lowering where appropriate, and consideration of cascade screening in family members.⁶

As the authors appropriately acknowledge, the present report also has several limitations. A single case report cannot establish causality, and it would be simplistic to attribute all disease progression in this patient solely to high lipoprotein(a). Residual inflammatory risk may also have contributed because hsCRP was elevated at presentation and remained high at follow-up. Importantly, individuals with concomitant high lipoprotein(a) and elevated hsCRP have the highest risk of ASCVD, compared with individuals with only elevations of one or the other.¹³ A further limitation is the reporting of lipoprotein(a) in different units at baseline and follow-up, specifically mg/dL initially and nmol/L subsequently, which prevents direct comparison.²

Even so, the overall message is clear. The current absence of an approved lipoprotein(a)-specific therapy is not an argument against testing; rather, it is an argument for more systematic testing. It is also particularly relevant in cases such as the present one, where age, sex, and standard lipid measurements could create a false sense of security. Failure to measure lipoprotein(a) in such patients risks missing the overall picture and may result in severe underestimation of absolute risk.¹

For readers of JACC: Case Reports, the take-home message is straightforward: measure lipoprotein(a) early in all, ideally at the time of the first lipid profile. At a time where measurements are lacking in most, prioritize measurements in patients with premature or otherwise unexplained coronary disease. Be aware, that a high lipoprotein(a) measurement identifies not only an individual with high lipoprotein(a), but a family with high lipoprotein(a), because levels are primarily genetically determined. Interpret the lipoprotein(a) laboratory result in the context of overall risk and use that information to intensify management of the risk factors that can already be treated today (Figure 1).

Figure 1.

High Lp(a) in Cardiovascular Disease: Measure Early and Act Early

High Lp(a) is a common, causal, and genetically determined cardiovascular risk factor that may contribute to premature and progressive coronary artery disease. Lp(a) measurement is actionable now because it refines risk stratification and supports earlier, more intensive preventive management, even before Lp(a)-specific therapies become widely available. Lp(a) = lipoprotein(a). Created using biorender.com.

Funding Support and Author Disclosures

Dr Kamstrup has received lecture honoraria or consultancies from Amgen, AstraZeneca, Lilly, Medscape, Novartis, PCSK9/lipoprotein(a) Forum, Physicians' Academy for Cardiovascular Education, Silence Therapeutics. Dr Thomas has received lecture honoraria and/or consultancies from Amgen, Novartis, and Novo Nordisk.