Lipoprotein(a) levels and cardiovascular events in individuals under 40: a systematic review

Background: Elevated lipoprotein(a) (Lp(a)) is an inheritable risk factor for atherosclerotic cardiovascular disease (ASCVD). Young individuals (<40 years) experiencing cardiovascular events often lack traditional risk factors, prompting interest in Lp(a)'s contribution. We systematically reviewed evidence on Lp(a) levels and cardiovascular events in people under 40. Methods: We searched MEDLINE, Web of Science, and Scopus (2013–2023) for studies examining Lp(a) in relation to cardiovascular outcomes in young populations. Inclusion criteria were English-language human studies in the past 10 years involving individuals <40 years with cardiovascular events, reporting Lp(a) levels or elevations. Two reviewers screened and selected studies, extracting data on Lp(a) concentrations, prevalence of elevated Lp(a), and cardiovascular outcomes. Quality was assessed qualitatively; due to heterogeneity, meta-analysis was not performed. Results: We found 6,812 records (2,137 in MEDLINE, 2,845 in Web of Science, and 1,830 in Scopus), and 1,504 duplicates were removed. All titles and abstracts were screened, and 62 articles were reviewed in full. Fifteen studies met the inclusion criteria and were qualitatively synthesized in this review. These included 9 observational studies (case–control, cohort, and cross-sectional designs) and 2 meta-analyses. Sample sizes ranged from 130 to 100,540 participants. Approximately one-third of young patients with a cardiovascular event had elevated Lp(a) levels (commonly defined as >30–50 mg/dL). Lp(a) elevations were significantly more frequent in young patients with myocardial infarction or stroke than in age-matched controls. Risk association: Elevated Lp(a) conferred a 2- to 3-fold higher risk of premature ASCVD events in most studies. The excess risk was most pronounced in individuals <45 years and attenuated with older age. A large meta-analysis (51 studies, ~100,000 patients) confirmed that elevated Lp(a) doubles the risk of composite ASCVD outcomes, especially coronary disease, in young populations. The association with ischemic stroke was weaker; one meta-analysis found no significant link in younger cohorts, but a focused analysis of young stroke patients showed Lp(a) ≥30 mg/dL was 43–61% more likely in cases than controls. Coexisting factors: About 20% of young MI patients had familial hypercholesterolemia (FH), and these patients showed higher Lp(a) levels and earlier events. Combined hyperlipidemia (elevated LDL and triglycerides) was present in ~15% and often accompanied elevated Lp(a). Elevated Lp(a) in young patients was associated with more severe coronary disease: for example, multivessel coronary involvement was more common in young MI patients with high Lp(a). Conclusions: In individuals under 40, elevated Lp(a) is prevalent and strongly associated with premature cardiovascular events, especially myocardial infarction. Young patients with ASCVD are significantly more likely to have high Lp(a) than their peers without events. High Lp(a) appears to triple the risk of early-onset coronary disease and is linked to more extensive atherosclerosis in this age group. These findings support measuring Lp(a) in young patients with ASCVD or a family history of early events. Ongoing trials of Lp(a)-lowering therapies will clarify whether reducing Lp(a) can improve outcomes in this population.