The most striking figure to emerge from this study is the prevalence of clinically meaningful Lp(a) elevation: 38.7% of ACS patients had Lp(a) levels above 100 nmol/L, the threshold endorsed by the National Lipid Association as a marker of substantially increased cardiovascular risk,2 and 21.1% exceeded 175 nmol/L, the eligibility criterion for the ongoing Lp(a)HORIZON phase III trial evaluating pelacarsen.3 Applying the more conservative European Atherosclerosis Society (EAS) threshold of 75 nmol/L, nearly half the cohort (46.1%) would be considered at high risk.4

The cohort's median Lp(a) of 62.0 nmol/L (IQR 18.4–153.8) is substantially higher than values reported in general population samples (approximately 19.6 nmol/L) and also exceeds the median of 42.0 nmol/L observed in a large multinational cohort of established ASCVD patients spanning 48 countries.5,6 Whether this reflects a genuine excess in the Portuguese ACS population, characteristics specific to the center, or, as is more likely, the selection bias inherent in opportunistic sampling, remains an important open question that requires further study.

These figures have a direct therapeutic implication. Neither statins nor ezetimibe meaningfully modify Lp(a) concentrations,7,8 and the present data confirm this in practice: patients on high-intensity statin therapy, alone (p-trend=0.032) or combined with ezetimibe (p-trend=0.014), tended to have higher, rather than lower Lp(a) levels. This almost certainly reflects confounding by indication, whereby higher-risk patients receive more intensive lipid-lowering therapy, but it also serves as a reminder that optimizing LDL-C leaves Lp(a)-driven residual cardiovascular risk unaddressed.9

Lp(a) levels showed no significant association with any individual traditional cardiovascular risk factor: hypertension, diabetes mellitus, dyslipidemia, smoking, or obesity. The correlations with LDL-C, HDL-C, total cholesterol, and triglycerides were all non-significant.1 Crucially, this independence held across all traditional cardiovascular risk factor burden categories: from patients with no risk factors to those carrying all five, median Lp(a) did not differ.

This finding is not unexpected. More than 90% of inter-individual variation in Lp(a) is genetically determined by the LPA gene, with concentrations largely established by the time of early childhood and unresponsive to the metabolic and lifestyle derangements captured by conventional risk scores.9,10 This independence has been confirmed in large population-based datasets, including a UK Biobank study of over 460 000 individuals.5 The operational implication is clear: Lp(a) screening cannot be restricted to patients with the greatest conventional risk burden. Only 11% of patients with Lp(a) levels >100 nmol/L in this cohort had a recorded family history of cardiovascular disease, which further weakens the value of family history as a criterion to guide Lp(a) testing. A secondary finding that warrants further investigation is the trend toward lower Lp(a) in patients with a history of atrial fibrillation or atrial flutter (p-trend = 0.028), which reached statistical significance at the 75 nmol/L (p = 0.016) and 175 nmol/L (p = 0.029) thresholds. This finding is in the opposite direction to results from a large observational and Mendelian randomization study suggesting a positive association between genetically elevated Lp(a) and atrial fibrillation risk.11 Whether the present inverse signal reflects a true biological relationship or differential referral and testing patterns within this opportunistically sampled cohort requires prospective evaluation.

Women in this cohort had higher Lp(a) levels than men overall (p-trend = 0.014): 47% of women exceeded the 100 nmol/L threshold versus 37% of men, and the proportion of women rose to 28% above 175 nmol/L compared with 17% in the lower-range group (p = 0.030). The sex difference was most pronounced and reached statistical significance, specifically in the subgroup of patients with no traditional cardiovascular risk factors (p = 0.003).1

The postmenopausal rise in Lp(a) concentrations is well documented. Simony et al., drawing on the Copenhagen General Population Study, reported mean Lp(a) levels 17–27% higher in postmenopausal women than in age-matched men, with partial reversal during hormone replacement therapy.12 The present findings are directionally consistent with this literature. However, the clinical interpretation requires caution: the cohort was only 19.6% female (76 women in total), and the subgroup without any traditional cardiovascular risk factors comprised 12 women. It is important to note that it was not reported how many of these women had elevated Lp(a) levels). With such limited numbers, the p = 0.003 result, while statistically significant, carries wide confidence intervals and limited precision.

The substantive clinical message̶women without conventional risk factors represent an underscreened population with high Lp(a) prevalence̶is plausible and consistent with evidence from larger prospective studies.6,13 However, the magnitude of the sex difference, and its independence from menopause status, hormone use, and age, cannot be established from these data. Larger sex-stratified prospective studies remain essential before this signal can be reliably translated into sex-specific screening recommendations.

Despite its limitations, this study makes a genuine contribution to the field. The finding that a single-center cohort with opportunistic testing identifies more than one in five ACS patients above the eligibility threshold for novel Lp(a)-lowering therapy3 reinforces the clinical urgency of embedding systematic Lp(a) measurement into ACS care pathways. As the therapeutic pipeline for Lp(a)-lowering agents advances through phase III evaluation,15 identifying eligible patients is now a clinical priority.

The call for universal Lp(a) screening at the time of ACS admission, endorsed by both the EAS and the European Society of Cardiology,4,16 is supported by this study's central observation: there is no clinical characteristic, risk factor pattern, or lipid parameter that reliably predicts who will have elevated Lp(a). Opportunistic, clinician-driven testing will inevitably leave many high-risk patients undetected. Prospective, protocol-driven registries are needed that measure Lp(a) universally in ACS, capture clinical outcomes, and include adequate numbers of women and diverse ethnic groups to generate sex- and population-specific data.

The study by Carrapa et al. conveys three key points: Lp(a) levels are independent of traditional risk factors; they are higher in women, especially those without conventional risk factors; and Lp(a) cannot be predicted using any standard clinical characteristics. These observations, along with the high prevalence of elevated Lp(a) in this cohort, make a strong case for universal screening upon admission for ACS. As Lp(a)-targeted therapies enter the clinical arena, identifying the patients most likely to benefit is no longer just a research priority—it is now an urgent clinical imperative.

None declared.

The authors have no conflicts of interest to declare.