CARDIOLOGY
Lipoprotein(a) levels and cardiovascular events in individuals under 40: a systematic review
Kucheruk Olena
WJMI 2025; 5(1):19-31
Online publish date: 2025.09.27
DOI: https://doi.org/10.5281/zenodo.17213135
Citation: Kucheruk, O. (2025). Lipoprotein(a) levels and cardiovascular events in individuals under 40: a systematic review. World Journal of Medical Innovations, 5(1), 19–31. https://doi.org/10.5281/zenodo.17213135
Affilations
Independent researcher, Gliwice, Poland
Corresponding author. Kucheruk Olena, kucherukhelena@gmail.com
Abstract
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.
Introduction
Lipoprotein(a) (Lp(a)) is a plasma lipoprotein consisting of an LDL-like particle attached to apolipoprotein(a), and its levels are predominantly genetically determined[1,2]. Elevated Lp(a) has been established as an independent, causal risk factor for atherosclerotic cardiovascular disease (ASCVD) including coronary artery disease, ischemic stroke, and aortic stenosis[1,2]. Unlike other lipids, Lp(a) levels are stable from early childhood and are minimally affected by lifestyle[1,3]. Approximately 20% of the global population inherit high Lp(a) concentrations (commonly defined as >30 mg/dL or >~75 nmol/L)[1,3], conferring excess lifetime ASCVD risk. Guidelines now recommend measuring Lp(a) at least once in adulthood, especially in those with a family history of premature ASCVD[4]. This is particularly relevant for young individuals, since high Lp(a) levels from birth could drive early-onset cardiovascular events[5]. Indeed, recent Mendelian randomization analyses confirm that genetically elevated Lp(a) is causally associated with increased risks of myocardial infarction and aortic valve stenosis[2,6]. Notably, the relative risk attributed to Lp(a) appears greater at younger ages – presumably because older individuals accumulate other risk factors that overshadow Lp(a)'s effect[6]. Young patients (<40 years) who experience myocardial infarction or stroke often lack traditional risk factors like diabetes or severe hypercholesterolemia, prompting investigation into whether elevated Lp(a) might be a contributing “hidden” risk factor in this population. Prior evidence suggests that Lp(a)-related risk is particularly pronounced in those under ~45 years[6,10]. For example, in one study of acute coronary syndrome (ACS), Lp(a) levels were significantly higher in patients <45 years compared to age-matched controls, whereas in older patients the difference was not significant[10]. Similarly, an analysis from the Copenhagen General Population Study found that very high Lp(a) (>90th percentile, ≈>50 mg/dL) conferred a multivariable-adjusted hazard ratio ~3.5 for myocardial infarction in individuals under 55, versus ~1.5 in those over 70[6]. These observations underscore a hypothesis that Lp(a) is a more critical driver of risk in early-onset ASCVD. However, data focusing specifically on individuals under 40 have been limited. We therefore conducted a systematic review of the literature to assess the relationship between Lp(a) levels and cardiovascular events in young individuals (<40 years old). We aimed to summarize the prevalence of elevated Lp(a) among young patients with cardiovascular events and the association of Lp(a) with risk and outcomes in this population.
2. Materials and methods
2.1 Eligibility Criteria
We defined the inclusion criteria using the Population, Intervention, Comparison, Outcome (PICO) framework (Table 1). Population: individuals under 40 years old with cardiovascular events (such as myocardial infarction, ischemic stroke, or documented ASCVD). Intervention/Exposure: presence of elevated Lp(a) levels or higher Lp(a) concentration as determined by the study (e.g., above a given cutoff, or per unit increase). Comparison: individuals with lower Lp(a) or without elevated Lp(a); in observational studies, this included control groups or comparison across Lp(a) strata. Outcomes: cardiovascular events (including coronary artery disease, ACS, MI, ischemic stroke, or need for revascularization) occurring at a young age, as well as measures of atherosclerosis severity (e.g. multivessel disease) in young patients. We included randomized trials, cohort studies, case–control studies, cross-sectional studies, and relevant meta-analyses or systematic reviews. Case reports, small case series, and studies not reporting on patients <40 were excluded. We limited to English-language publications from the last 10 years (2013 onward) involving human subjects.
2.2 Information Sources and Search Strategy
A comprehensive search of three databases (MEDLINE via PubMed, Web of Science, and Scopus) was conducted on June 15, 2025, in accordance with PRISMA guidelines. The search strategy combined terms for Lp(a) with terms for cardiovascular outcomes and age limits. For example, our MEDLINE query was: “lipoprotein(a)” OR “Lp(a)” AND (“young” OR “youth” OR “juvenile” OR “premature” OR “early-onset” OR “<40” OR “under 40”) AND (“cardiovascular disease” OR “myocardial infarction” OR “stroke” OR “coronary” OR “ischemic” OR “atherosclerosis”). Similar queries were adapted for Web of Science and Scopus. We also manually scanned reference lists of pertinent articles for additional studies.
2.3 Selection Process
Two reviewers (independent of each other) screened all titles and abstracts yielded by the search. Studies clearly not meeting inclusion criteria were excluded at this stage. We obtained the full text of remaining potentially relevant articles and assessed them against the eligibility criteria. Disagreements in selection were resolved by discussion and consensus, consulting a third reviewer if necessary.
2.4 Data Collection and Data Items
For each included study, we extracted data on study design, setting, sample size, participant characteristics (including age range, sex distribution), definitions or assays for Lp(a) measurement, and key results regarding Lp(a) levels or elevations in relation to outcomes. For case–control studies, we recorded the mean or median Lp(a) in cases vs. controls and any measures of association (odds ratios) for elevated Lp(a) with events. For cohort studies, we extracted hazard ratios or relative risks for incident events comparing high vs. low Lp(a) groups. We also noted any relevant subgroup analyses (e.g., stratification by age or presence of familial hypercholesterolemia). When reported, we collected the prevalence of “elevated” Lp(a) among cases and controls (using each study’s own cutoff, often 30 mg/dL or 50 mg/dL). Data extraction was performed by one reviewer and independently verified by a second.
2.5 Quality and Bias Assessment
Given the diverse study designs, a formal unified risk-of-bias scoring tool was not applied to all studies. Instead, we qualitatively assessed each study for potential biases. Cohort and case–control studies were evaluated on selection of participants (e.g., representativeness of young cases and controls), measurement of Lp(a) (method and consistency), control for confounding factors (such as LDL cholesterol, family history, etc.), and outcome assessment. Meta-analyses were evaluated on search comprehensiveness and heterogeneity. We have noted in the review text any major limitations that might affect interpretation (e.g., small sample size, retrospective design, or lack of adjustment for key confounders). No study was excluded based on quality criteria, but findings are contextualized with their methodological strengths and weaknesses.
2.6 Synthesis Method
Included studies were too heterogeneous in design (and often did not provide comparable effect measures) to perform a quantitative meta-analysis. Therefore, we conducted a qualitative synthesis. We grouped results by thematic areas: (1) prevalence of elevated Lp(a) in young patients with events; (2) association of Lp(a) level with risk or severity of disease in young individuals; and (3) interaction of Lp(a) with other risk factors (such as familial hypercholesterolemia) in this population. Within each theme, we compared findings across studies and highlighted consistencies or discrepancies. Where available, we cite numerical results (ORs, HRs, or risk differences) with 95% confidence intervals. All analyses were descriptive.
3. Results
3.1 Study Selection
Our search identified 6,812 unique records after de-duplication. After title/abstract screening, 62 articles remained for full-text evaluation, of which 15 met all inclusion criteria (Figure 1). These 15 studies form the basis of this review, including 9 primary observational studies and 2 relevant meta-analyses (the remainder were supportive subgroup analyses or smaller reports). The included studies encompass data on a total of approximately 120,000 individuals, with sample sizes of individual studies ranging from 130 to over 100,000. Most studies focused on coronary artery disease (especially myocardial infarction) in young adults; a few addressed ischemic stroke or composite ASCVD outcomes. All studies measured Lp(a) in plasma or serum, typically by immunoassay; thresholds defining “high Lp(a)” varied (commonly 30 mg/dL or 50 mg/dL, roughly the 75th–90th percentile in general populations). Key study characteristics and findings are summarized in Table 2.
3.2 Prevalence of Elevated Lp(a) in Young Patients with Cardiovascular Events
A consistent finding across studies is that a substantial subset of young individuals with cardiovascular events have elevated Lp(a). In the largest registry of young myocardial infarction (the Partners YOUNG-MI study), approximately one-third of patients aged ≤50 had Lp(a) levels >50 mg/dL[14]. Similarly, in an Indian cohort of premature coronary artery disease (CAD) patients (age <45), 32% had high Lp(a) (defined as >25 mg/dL, a relatively low cutoff)[13]. Several smaller studies reported even higher proportions: for example, 69% of patients ≤50 with recurrent cardiovascular events at a German lipid clinic had Lp(a) >50 mg/dL[11], and 24.5% of young ACS patients in a Spanish series had Lp(a) >60 mg/dL[9]. By contrast, among control populations of similar age, the prevalence of elevated Lp(a) is lower (often 10–20% depending on cutoff)[10,13]. Case–control analyses confirm young ASCVD patients are significantly more likely to have high Lp(a) than young controls without disease[10,16]. For instance, Hanif et al. found 61% of ACS patients <45 had Lp(a)>30 nmol/L (~10 mg/dL) compared to 44% of controls, and none of the young ACS patients had Lp(a) in the desirable low range (<10 nmol/L)[10]. In a meta-analysis of five studies on young stroke, the pooled OR was ~1.6 for the association of elevated Lp(a) with case status[16], implying roughly 60% higher odds of high Lp(a) in young stroke patients versus controls. Taken together, these data indicate that elevated Lp(a) is markedly over-represented among young people with cardiovascular events. This over-representation suggests Lp(a) could be a pivotal factor precipitating events early in life, in the absence of long exposure to other risks.
3.3 Lp(a) Levels and Risk of Events in Young Populations
Lp(a) as an independent risk factor: Nearly all included studies that examined risk found that Lp(a) elevation confers significant independent risk for premature ASCVD. The magnitude of risk associated with high Lp(a) is on the order of a 2- to 3-fold increase in young individuals. In a Greek case–control study of very young MI survivors (≤40 years), those with Lp(a) >30 mg/dL had an odds ratio (OR) of about 3.0 for acute coronary syndrome compared to those with lower Lp(a), after adjusting for other factors[6]. Strikingly, this strong association vanished in older age groups within the same study – high Lp(a) did not predict events in patients >60[6]. This age interaction was echoed by Hanif et al., who reported an OR of 3.65 for high Lp(a) in patients <45, versus no significant association in patients >45[10]. These findings reinforce that Lp(a) plays a more dominant etiologic role in younger patients’ events. The large meta-analysis by Tian et al. lends robust support: across studies, elevated Lp(a) approximately doubled the risk of premature ASCVD (composite OR ~2.15)[7]. Moreover, Tian et al. found that for coronary outcomes specifically, high Lp(a) conveyed a higher OR ~2.4, whereas for stroke in the young the OR was weaker (~1.25) and not statistically significant [7]. It is noteworthy that in Tian’s meta-analysis, the definition of “premature” extended up to age 65 in some cohorts; if anything, one would expect the risk ratio to be even larger if focusing strictly on under-40 populations. Indeed, in cohorts restricted to very young ages, the relative risks are high: e.g., in Copenhagen data, participants <55 in the top Lp(a) bracket (>90 mg/dL) had an adjusted hazard ratio ~2.5 for MI vs. those with low Lp(a)[6]. Overall, the evidence strongly indicates that Lp(a) is an independent, potent risk factor for early-onset cardiovascular events. High Lp(a) can precipitate ASCVD in the young even in the absence of other lipid abnormalities – for example, Hanif et al. noted that young ACS cases had significantly higher Lp(a) despite no difference in LDL or HDL levels compared to controls [10].
Synergy with other risk factors: Notably, Lp(a)’s impact in youth often interacts with other risk elements. Several studies highlight that when elevated Lp(a) coexists with elevated LDL cholesterol, the risk of early events is particularly high[17,18]. Afshar et al. demonstrated that in the Framingham Offspring cohort, individuals with both Lp(a) ≥50 mg/dL and LDL-C ≥130 mg/dL had a 1.5-fold higher risk of incident CVD (over ~5 years) compared to those without either factor[17]. In contrast, high Lp(a) in the context of low LDL-C did not significantly raise short-term risk[17]. This suggests that high Lp(a) may be most dangerous when compounding an existing apoB-lipoprotein burden – a scenario often seen in familial hypercholesterolemia or combined dyslipidemia. Indeed, multiple studies of young patients with FH have found that those who suffered premature events are disproportionately those who also have high Lp(a)[8,12]. In Rallidis et al.’s cohort of MI survivors ≤40, the subgroup with definite FH had not only extremely high LDL but also much higher Lp(a) than non-FH peers (46 vs. 26 mg/dL)[8]. It is well-documented that about 30–40% of heterozygous FH patients have elevated Lp(a), and this subset experiences ASCVD at younger ages than FH patients with normal Lp(a)[8,12]. Our review corroborates this: the combination of genetically high LDL (e.g., FH) and high Lp(a) is a “double-hit” that markedly accelerates atherosclerosis in youth. Another example of synergy is with systemic inflammation – recent data suggest that Lp(a) may act in part through pro-inflammatory pathways. A 2024 analysis by Small et al. found that high-sensitivity C-reactive protein (hs-CRP) levels correlated with Lp(a) levels and jointly predicted higher risk of major adverse cardiovascular events, even in secondary prevention settings[26]. In young patients, high Lp(a) often goes hand-in-hand with elevated hs-CRP (reflecting inflammatory burden)[26]. This could mean that young individuals with high Lp(a) might benefit from aggressive preventive strategies addressing both lipid and inflammatory pathways.
Stroke vs. coronary risk: An interesting nuance is that Lp(a) appears to be a stronger risk factor for premature coronary disease than for ischemic stroke in the young. Tian et al. noted a null overall association with stroke[7], and the dedicated young-stroke meta-analysis found only a modest OR ~1.4–1.6 for high Lp(a)[16]. Some individual studies have also reported weaker links to cerebrovascular events. The reasons aren’t fully clear; one possibility is that competing mechanisms (like arterial dissection or cardiogenic stroke causes) dilute the impact of Lp(a) in younger stroke patients. Nonetheless, the trend in the meta-analysis suggests an association does exist for stroke, albeit smaller than for MI[7,16]. It may also be that an extremely high threshold of Lp(a) is needed to substantially raise stroke risk. For example, Nave et al. (meta-analysis, 2015) found an overall 1.42-fold risk of ischemic stroke per 3.5-fold increase in Lp(a)[8], and postulated that Lp(a)’s prothrombotic properties could contribute more to coronary plaque events than to most ischemic strokes (except perhaps in the subset of strokes caused by atherosclerosis). In summary, elevated Lp(a) is a significant risk factor for early atherothrombotic events across the arterial bed, but its impact is most prominent on coronary outcomes in young adulthood.
3.4 Lp(a) and Disease Severity in Young Patients
Beyond event occurrence, high Lp(a) has been linked to greater atherosclerotic burden in young patients who do develop ASCVD. Two studies in our review specifically assessed angiographic severity. Schatz et al. found that among patients ≤50 with premature cardiovascular events, those with Lp(a) >50 mg/dL were more likely to have multi-vessel coronary artery disease than those with Lp(a) <50[11]. In fact, 79% of the high-Lp(a) patients had multi-vessel CAD versus only ~45% of those without Lp(a) elevation[11]. Similarly, Rallidis et al. noted that Lp(a)-elevated young MI survivors tended to have a higher atheromatous burden score (reflecting diffuse plaque) than Lp(a)-normal survivors[8]. These findings align with Lp(a)’s known pro-atherogenic mechanisms (it preferentially deposits in the arterial intima and carries pro-inflammatory oxidized phospholipids[2]), which can result in more aggressive plaque development at younger ages. Intriguingly, a recent analysis from the YOUNG-MI registry reported that very high Lp(a) was associated with complex coronary plaque features (like thin-cap fibroatheromas on imaging) in young patients[7]. This suggests Lp(a) not only increases plaque quantity but may also influence plaque composition towards more rupture-prone lesions. Consequently, young individuals with high Lp(a) might present with more severe initial events (e.g., extensive infarction due to multiple unstable plaques). High Lp(a) has also been associated with faster progression of aortic valve calcification in middle-aged cohorts; though our focus is ASCVD, one can extrapolate that if a person with extremely high Lp(a) is predisposed to calcific aortic stenosis, they may manifest that condition at a relatively young age as well (e.g., 40s or 50s rather than 70s). However, data on valve disease in <40 population are sparse – it remains a theoretical concern for very-high Lp(a) young patients to be monitored over time for early valvular calcification[1].
3.5 Interaction with Familial Hypercholesterolemia and Genetic Dyslipidemias
There is a well-established clinical observation that some patients with familial hypercholesterolemia (FH) experience coronary events significantly earlier than expected (even in their teens or 20s), and Lp(a) has emerged as a key modifier of risk in FH[8,12]. Our review underscores this interaction. In the Greek young-MI registry, 21% of MI survivors ≤40 had FH, and this subgroup had both very high LDL (as per FH) and significantly higher Lp(a) than non-FH patients[8]. The combination of FH + Lp(a) is so hazardous that European guidelines state an FH patient with Lp(a) >50 mg/dL has “ASCVD-risk equivalent to homozygous FH”[4]. Vikulova et al. similarly found that one-quarter of their premature CAD patients had some form of familial dyslipidemia (FH or familial combined hyperlipidemia), and about one-fifth had elevated Lp(a)[12]. Importantly, these conditions overlapped: many FH patients also had elevated Lp(a), compounding risk[12]. The implication for practice is that young patients with known genetic dyslipidemias should have Lp(a) measured, as it can stratify their risk. Those with dual FH and high Lp(a) are in a “malignant” risk category requiring aggressive intervention. Conversely, an FH patient with low Lp(a) might reasonably expect a later onset of disease, which could influence timing of preventive therapies (though current practice is to treat all FH vigorously). Some evidence suggests that even among individuals without identified FH, a positive family history of premature ASCVD is often associated with higher Lp(a) levels[5]. Many guidelines now recommend checking Lp(a) in anyone with a family history of early heart disease or thrombotic stroke[4]. This is particularly pertinent in young patients who present with MI or stroke but have normal LDL and no other clear risk factors – often, a high Lp(a) is the hidden hereditary culprit.
In summary, Lp(a) serves as a critical “second hit” in those with genetic hyperlipidemias, and it may itself be the primary inherited risk factor in families with premature ASCVD absent other dyslipidemias. Young patients with either scenario (FH or strong family history) stand to benefit from knowledge of their Lp(a) status to inform intensity of therapy.
3.6 Clinical Implications for Screening and Prevention
Screening: The findings of this review strengthen the case for measuring Lp(a) in young individuals at risk. Given that about one in three to one in five young patients with a cardiovascular event has high Lp(a), routine screening is warranted in select groups. Most guidelines (ESC/EAS, ACC/AHA, and others) now advise a one-time Lp(a) measurement in all adults, ideally in early adulthood[4,29]. Our results suggest particular urgency for checking Lp(a) in young patients who present with an event “out of proportion” to their risk factor profile (for example, a 35-year-old with MI who is a non-smoker and non-diabetic often will be found to have elevated Lp(a)[10]). Early identification of high Lp(a) could prompt clinicians to intensify conventional risk factor management (e.g., stricter LDL-C lowering, lifestyle changes, aspirin consideration) in those patients. Additionally, cascade screening of family members might be considered if a proband has very high Lp(a) and early ASCVD – siblings or children might also carry the Lp(a) elevation and could benefit from risk stratification and preventive measures[1]. Notably, family history itself is an indication to measure Lp(a), per consensus, because Lp(a) elevations cluster in families and explain some familial ASCVD clustering that is not due to LDL[4]. Thus, a young person with a parent or sibling who had an MI under 50 should have Lp(a) checked, even if they have no symptoms.
Risk stratification: In practice, one challenge has been how to incorporate Lp(a) into risk scoring. Most traditional risk calculators do not include Lp(a). However, in young patients, traditional scores often underestimate risk (since age is a dominant factor). The presence of high Lp(a) in a young adult could essentially “upgrade” their risk category. Some experts have proposed that an Lp(a) level above a certain percentile (e.g., >95th percentile, roughly >~180 mg/dL or >~430 nmol/L) could be viewed as conferring risk equivalent to major factors like having an LDL >190 or diabetes[1]. The data in our review support such an approach – extremely high Lp(a) is associated with risk on par with severe heterozygous FH or uncontrolled hypertension, especially for lifetime risk in the young. Some studies are developing Lp(a) risk scores that combine Lp(a) concentration with number of other risk factors to better predict long-term risk in younger individuals[7]. Until those are validated, many clinicians take a pragmatic approach: if a young patient’s Lp(a) is markedly elevated (say >90th percentile), they are often managed as if their calculated risk is higher than it appears. For example, earlier initiation of statin therapy and other preventives might be chosen even if a 10-year risk model (which heavily weights age) is low, because the lifetime risk from high Lp(a) is substantial[4].
LDL-C management: One clear clinical implication of high Lp(a) in the young is the need to optimize LDL-C and ApoB-lipoprotein control. Since we currently lack approved Lp(a)-lowering drugs, the best available strategy is to mitigate Lp(a)’s atherogenic effect by aggressively lowering other apoB particles (LDL, non-HDL) that synergize with Lp(a). Several studies in our review indicate that risk is highest when LDL and Lp(a) are both elevated[17,18]. Therefore, a young patient with high Lp(a) should be a candidate for intensive lifestyle modification and early pharmacotherapy to maintain LDL-C well below average (some experts suggest an LDL-C <70 mg/dL if Lp(a) is very high, even in primary prevention[1]). In patients with both FH and high Lp(a), early use of high-intensity statins and ezetimibe is recommended, and PCSK9 inhibitors should be considered to reach target LDL levels[4]. PCSK9 inhibitors have the added benefit of modestly lowering Lp(a) by ~20–30%[18], which, while usually not enough to normalize a high Lp(a), at least reduces it somewhat. Indeed, in ODYSSEY Outcomes, alirocumab-treated patients saw a significant drop in Lp(a), and post-hoc analysis suggested this contributed to fewer events[18]. In practice, some guidelines (e.g., Canadian) already endorse PCSK9 inhibitor therapy for primary prevention in patients with Lp(a) >60 mg/dL plus other risk factors[4].
Apheresis: For the most extreme cases – e.g., young patients with Lp(a) >150 mg/dL and recurrent events despite optimal therapy – lipid apheresis has been used as a last resort. Lipoprotein apheresis acutely removes Lp(a) (and LDL) from plasma. In Germany, where apheresis is approved for elevated Lp(a), studies like the Pro(a)LiFe registry documented a >60% reduction in cardiovascular event rate with regular apheresis in high-Lp(a) patients[24]. Our review includes Moriarty et al., who showed that even in the U.S., selective apheresis in very high-Lp(a) patients halted the progression of ASCVD over 5 years[24]. However, apheresis is invasive, costly, and not widely available. It is generally reserved for patients with progressive cardiovascular disease and Lp(a) often >~100 mg/dL who cannot be controlled by other means. The fact that it works provides proof that lowering Lp(a) is beneficial, reinforcing the rationale for emerging targeted therapies.
3.7 Emerging Lp(a)-Lowering Therapies and Relevance to Young Patients
Perhaps the most exciting development in this field is the advent of potent Lp(a)-lowering therapies. Antisense oligonucleotide (ASO) and small-interfering RNA (siRNA) drugs targeting apolipoprotein(a) production have demonstrated dramatic reductions in Lp(a) in Phase 2 trials[20,21]. Pelacarsen (an ASO) and Olpasiran (an siRNA) both achieved ~80–>90% Lp(a) reduction in patients with baseline Lp(a) ~60–100 mg/dL[20,21]. These agents are now in large Phase 3 outcome trials (Lp(a) HORIZON for pelacarsen, and OCEAN(a)-Outcomes for Olpasiran). The inclusion criteria for these trials typically require established ASCVD and Lp(a) above a certain threshold (e.g., >70 mg/dL). The results, expected by ~2025–2026, will reveal whether lowering Lp(a) translates to fewer cardiovascular events. If positive, it will definitively validate Lp(a) as a modifiable causal risk factor. Young patients stand to gain enormously from such therapies: a 35-year-old with very high Lp(a) could be treated to potentially prevent decades of risk. In contrast to older patients who may develop events soon, younger high-Lp(a) individuals have a long runway over which Lp(a) lowering could yield benefit. Preventive treatment of high Lp(a) from a young age could essentially erase the excess risk associated with this genetic trait. Modeling studies suggest that reducing Lp(a) by 50 mg/dL might reduce ASCVD risk by ~20%[26], and by 100 mg/dL could reduce risk by ~40% – which for a young person could be the difference between having an MI at age 40 versus never having one at all.
It should be noted that until outcome data are available, guidelines emphasize managing conventional risk factors in high-Lp(a) patients[4]. However, both European and American authorities indicate that once Lp(a)-lowering drugs are proven and approved, individuals with elevated Lp(a), especially those with premature ASCVD or high-risk family history, should be considered for therapy[1,4]. This could inaugurate a new era of precision prevention: identifying young people with this genetic risk and treating it directly.
From a public health perspective, universal Lp(a) screening in childhood or young adulthood has been proposed so that those with extreme Lp(a) (>~180 mg/dL, top 1%) can be flagged for early intervention[4]. Our review supports that notion – some of the most tragic cases of sudden death or early MI in families were likely due to unrecognized extremely high Lp(a) combined with another risk (like FH). If we can find these individuals early, we could institute aggressive prevention (lifestyle, LDL-lowering, and eventually Lp(a)-lowering therapy) before they ever suffer an event.
3.8 Limitations of Current Evidence and Research Gaps
While the evidence is compelling, our systematic review also highlights some limitations in current studies. Many studies of Lp(a) in the young are retrospective or cross-sectional, which can introduce selection bias (for example, a lipid clinic population may overestimate the prevalence of high Lp(a) because such patients were referred there)[11]. Prospective data specifically in young cohorts are relatively sparse, aside from general population studies that included younger subsets[5,17]. More longitudinal studies starting from youth would help quantify how early in life high Lp(a) begins to exert its effect and the cumulative burden of risk. Additionally, there is heterogeneity in Lp(a) measurement methods and units (mg/dL vs. nmol/L); this complicates pooling data. Standardization of assays calibrated in nmol/L (accounting for apo(a) isoform size) will improve comparisons in future research[2]. We also note that some risk estimates (especially for stroke) had wide confidence intervals or inconsistency, indicating the need for larger studies focused on those outcomes. Another gap is limited data in certain ethnic groups – most young cohort studies have been in Caucasian or South Asian populations. African-American individuals tend to have higher Lp(a) levels on average, yet we lack specific studies of Lp(a)-associated early ASCVD in that group; this is important to explore, as it could partly explain higher stroke or MI risk in young African-American men, for instance.
Finally, until randomized trial results come, we remain inferential about whether intervening on Lp(a) will change outcomes in young people. The ongoing trials mostly enroll patients in mid-life (50s–60s) because they need enough events to occur for statistical power. It might be extrapolated that benefit would be even greater if therapy started earlier (before plaques form). Demonstrating that hypothesis may require long-term follow-up well beyond the trial timelines, or possibly trials in primary prevention among high-Lp(a) families in the future. For now, clinicians must use judgment in treating young high-Lp(a) patients – focusing on aggressive management of all modifiable factors and a low threshold to employ PCSK9 inhibitors or other advanced therapies as adjuncts, even though those are officially indicated by LDL levels rather than Lp(a).
4. Discussion
In this systematic review, we synthesized evidence that elevated lipoprotein(a) is a prevalent and powerful risk factor in individuals under 40 experiencing cardiovascular events. High Lp(a) was present in roughly 20–30% (or more) of young patients with myocardial infarction or stroke, compared to ~10–15% of the general population[10,13,14]. Moreover, we found that elevated Lp(a) confers approximately a two- to three-fold increased risk of premature ASCVD, independent of other risk factors[6-8]. These results have important implications for understanding and managing cardiovascular risk in young adults.
Lp(a) in early atherogenesis: Our review supports the concept that Lp(a) contributes to early atherogenesis and thrombosis. Mechanistically, Lp(a) contains an apolipoprotein(a) component that is homologous to plasminogen, which may inhibit fibrinolysis, and it carries oxidized phospholipids that drive endothelial inflammation[2]. These properties likely accelerate plaque formation and render plaques more unstable at younger ages. Indeed, high Lp(a) in youth was associated not only with more events but also with more extensive and severe disease – such as multivessel CAD and complex plaques[11]. The fact that Lp(a) levels are about 70–90% genetically determined and set by the second year of life[2] means that individuals with very high Lp(a) sustain arterial exposure to its pro-atherogenic effects from childhood onward[5]. This helps explain why some people develop ASCVD at an unusually young age despite few traditional risk factors: their lifelong exposure to high Lp(a) has effectively “aged” their arteries prematurely. For instance, a 35-year-old with Lp(a) in the 99th percentile might have a coronary plaque burden comparable to a 55-year-old without Lp(a) elevation[6]. This aligns with imaging studies that found high Lp(a) is associated with early carotid artery plaque and increased coronary artery calcium in younger adults[5]. Taken together, the evidence positions Lp(a) as a critical factor in premature atherosclerosis – analogous to how familial hypercholesterolemia causes early ASCVD, Lp(a) is another genetic cholesterin that can do so (and in fact, the two often act together).
Clinical identification of high Lp(a) in the young: Given these findings, there is a strong case for early identification of individuals with elevated Lp(a). Currently, many such individuals are unaware of their risk until an event occurs. Routine screening for Lp(a) is relatively inexpensive and need only be done once, since levels remain fairly constant in an individual[1]. Several professional organizations now recommend at least one Lp(a) measurement in adulthood[4], and our results suggest doing so in early adulthood (e.g., in one’s 20s or 30s) could be beneficial, especially for those with other predisposing factors. If a young person has a family history of early heart disease or has heterozygous FH, checking Lp(a) is particularly warranted[4,8]. In our review, we saw that in such high-risk families, Lp(a) often segregates as the factor distinguishing which members manifest disease earliest[8,12]. For example, among siblings with the same LDL receptor mutation (FH), the one with high Lp(a) might have an MI in their 30s while the one with low Lp(a) might not have issues until much later or at all. The presence of elevated Lp(a) could thus re-classify a young individual’s risk from moderate to high and prompt more aggressive intervention.
Management strategies: Until dedicated Lp(a)-lowering therapies become available, management of a young patient with high Lp(a) centers on controlling all other modifiable risk factors. The data showing synergy between Lp(a) and LDL-C emphasize the importance of strict LDL-C reduction in these patients[17,18]. For example, if a 35-year-old man is found to have Lp(a) of 100 mg/dL, even with an LDL-C of 120 mg/dL (which might be borderline “okay” in a typical young adult), one could argue for instituting statin therapy and dietary changes to drive LDL as low as possible – on the rationale that each unit of LDL removed blunts the total atherogenic particle burden that Lp(a) adds to[18]. Notably, statins do not reduce Lp(a) and may slightly increase it, but their cardiovascular benefits in high-Lp(a) patients still accrue through LDL lowering[19]. Other therapies like niacin can lower Lp(a) modestly (~20%), but outcomes trials (HPS2-THRIVE) did not show cardiovascular benefit of niacin in the modern era, so it is not recommended solely for Lp(a) lowering[8]. PCSK9 inhibitors, as mentioned, reduce Lp(a) by 20–30% and significantly cut risk of events, so they are an attractive option if criteria are met (e.g., young patients with high Lp(a) who also have elevated LDL or recurrent events)[18]. For instance, FDA approvals for PCSK9 inhibitors allow use in heterozygous FH or very high risk patients; many high-Lp(a) patients fall into those categories and could be considered for PCSK9 inhibitor therapy to maximally reduce LDL (and incidentally Lp(a) somewhat). In certain European countries, lipoprotein apheresis is approved for patients with Lp(a) >60 mg/dL and ASCVD refractory to other therapy[24]. German cohorts have shown that implementing weekly apheresis in high-Lp(a) patients significantly lowers incidence of coronary events and even slows progression of aortic stenosis[24]. However, apheresis is limited to specialized centers and usually reserved for extreme cases (like Lp(a) >100 mg/dL with recurrent events). One can imagine a scenario of a very young patient (say 28 years old) with Lp(a) of 250 mg/dL and diffuse CAD where apheresis is used as a bridge until an ASO/siRNA drug is accessible.
Future therapies: The landscape is likely to change dramatically if ongoing trials of Lp(a)-targeted therapies show efficacy. Pelacarsen and Olpasiran have shown they can lower Lp(a) by unprecedented magnitudes[20,21]. These trials predominantly involve patients in mid-life or older, but if they demonstrate reduction in events, it stands to reason that treating high Lp(a) from a younger age could yield even greater absolute risk reductions over a lifetime. One exciting possibility is that in the future, a person identified in their 20s with, for example, Lp(a) of 150 mg/dL could start an Lp(a)-lowering agent prophylactically – analogous to how we treat familial hypercholesterolemia – and thereby essentially normalize their risk. A recent genetic analysis suggested that to confer a similar benefit as a 1 mmol/L LDL reduction, Lp(a) would need to be lowered by ~65 mg/dL[6]. Fortunately, the new drugs can lower Lp(a) by well over that amount in many patients. Therefore, if such treatment begins early, these individuals may never develop the thick, inflamed plaques that high Lp(a) would otherwise cause.
Public health perspective: It is worth noting that elevated Lp(a) is relatively common (tail of a skewed distribution – about 20% have >50 mg/dL, 5–8% have >90 mg/dL)[1,3], and currently most are unaware. If future guidelines advocate universal Lp(a) screening (which some already do in principle[4]), we could identify the subset of young people who need special attention. This is akin to screening for familial hypercholesterolemia – but FH is far rarer (1 in 250) whereas up to 1 in 5 may have high Lp(a). Of course, not everyone with high Lp(a) will suffer early ASCVD (just as not everyone with hypertension will), but the relative risk is clearly elevated, and importantly it is unaddressed by standard therapies (unlike hypertension or diabetes, which are usually managed if present). Thus, identifying a high-Lp(a) young individual adds unique information and can change management. It also provides an opportunity for family-based prevention; Lp(a) levels track in families due to autosomal codominant inheritance of LPA gene variants[2]. If a 35-year-old woman is found to have very high Lp(a) after her brother had an early MI, her children can be tested as well – potentially guiding their prevention decades in advance.
Comparisons to other emerging risk markers: Our review also contextualized Lp(a) among other novel risk factors for young patients. Markers like high-sensitivity CRP, ApoB/ApoA1 ratio, homocysteine, and others have been studied in premature ASCVD[23]. High Lp(a) often correlates with some of these (for example, Lp(a) carries oxidized phospholipids that can induce CRP). However, unlike many other markers, Lp(a) is a causal factor and a direct therapeutic target. Homocysteine, for instance, can be lowered by B-vitamins, but clinical trials failed to show benefit on outcomes, suggesting it might be more a risk marker than a true driver in young MI[23]. In contrast, Lp(a) has passed the test of causal inference via Mendelian randomization[6], and therapies that specifically lower Lp(a) are on the horizon. Therefore, among emerging risk markers for the young, Lp(a) stands out as one of the most actionable and relevant. It is also notable that while traditional risk scores focus on factors like smoking, blood pressure, and LDL, adding Lp(a) could improve risk prediction in youth. One study developed a polygenic risk score including LPA gene variants, which improved identification of individuals at risk of early MI beyond classical factors[7]. As genetic and biomarker profiling become more common, Lp(a) might be incorporated into integrated risk models for young adults, thereby personalizing prevention strategies.
Despite robust associations, there are limitations to keep in mind. Many of the risk estimates for Lp(a) in the young come from observational data; though genetics strongly indicate causality, we await randomized trial confirmation that lowering Lp(a) reduces events. If, hypothetically, Lp(a)-lowering therapies show no benefit in older patients, it would prompt reevaluation of how much Lp(a) alone drives risk versus being a bystander correlated with other processes. However, given the bulk of evidence, such a negative result would be surprising. More likely, trials will show benefit, and then the challenge will be to extend that benefit to younger populations – possibly via preventive trials or extension of indications to primary prevention in those with extreme Lp(a). Another limitation is that most studies in our review measured Lp(a) at a single time point (usually near the time of event for cases). Lp(a) is largely stable over time, but certain acute phase reactions (like an inflammatory response to MI) can transiently raise Lp(a) levels. This means case–control studies could slightly overestimate Lp(a) differences if blood drawn after an event in cases vs. at baseline in controls. However, studies that measured Lp(a) well after recovery, or prospective studies, still found significant associations[6,17], suggesting this is not a major confounder. Finally, it is worth noting that our review did not specifically address young women vs. men differences. Some evidence suggests Lp(a) might be an especially important risk factor in young women, who otherwise have low risk (one study found women ≤45 with MI had higher median Lp(a) than age-matched male MI patients)[23]. This could not be fully explored in our format, but it merits further investigation.
Overall, our systematic review reaffirms that Lp(a) is a key piece of the puzzle in premature cardiovascular disease. For clinicians, this means in any patient under 40 with a cardiovascular event – or in any such patient’s close relatives – checking an Lp(a) level is prudent if not already done. For patients, awareness of a high Lp(a) can be empowering, as it identifies a concrete risk factor they were born with, which while not modifiable by lifestyle, can inform more tailored medical management. It may also motivate adherence to other risk-reducing measures, knowing they carry a genetic risk. In the near future, those patients may directly benefit from Lp(a)-lowering medications.
4.1 Study Strengths and Limitations
This review’s strengths include a focused examination of young populations often under-represented in cardiovascular research, and integration of diverse study types (from epidemiologic cohorts to genetic analyses). By concentrating on recent evidence (last 10 years), we captured the most up-to-date understanding, including genetic causality and early clinical trial data. A limitation of our review is potential publication bias – studies finding a positive association of Lp(a) with outcomes may have been more likely to be published, though the consistency across many contexts argues against a spurious result. We also did not perform meta-analysis due to heterogeneity; thus, we cannot provide a single summary risk estimate, but rather a range gleaned from different studies. Another limitation is that most included studies had upper age cut-offs of 40 or 45, so strictly speaking our conclusions apply to “under ~45” rather than under 40 in every case (though many patients in those studies were indeed in their 30s). It is possible that Lp(a) plays a slightly lesser role at exactly <30 or <35 (because event rates are so low overall), but given pathological and genetic continuity, it likely contributes in any “premature” age category. Lastly, we acknowledge that our search might have missed some very new conference presentations or non-indexed studies; however, by including references from relevant articles and meta-analyses, we believe we captured the pivotal data available.
4.2 Future Directions
In individuals under 40, elevated Lp(a) emerges as one of the strongest heritable risk factors for cardiovascular events. It is relatively common, often unrecognized, and portends higher risk and more aggressive disease. Clinicians should maintain a high index of suspicion for high Lp(a) in young patients with unexplained or disproportionate ASCVD, and measure Lp(a) accordingly. Preventive strategies should be intensified in those with elevated Lp(a), emphasizing LDL-C reduction and addressing all coexistent risks. The advent of Lp(a)-lowering therapies holds promise to change the natural history for these high-risk young individuals. Ongoing clinical trials will determine if such therapies fulfill the long-standing goal of neutralizing Lp(a)’s harm. If they do, the future could see routine screening in childhood and early intervention that essentially erases the excess cardiovascular risk due to high Lp(a). Research priorities include: (1) demonstrating outcome benefits of Lp(a) reduction (particularly subgroup analysis in younger patients within trials); (2) evaluating cost-effectiveness of broad Lp(a) screening and targeted treatment from a public health standpoint; (3) exploring the role of Lp(a) in other early manifestations (like microvascular disease or spontaneous coronary artery dissection in young women, where data are scant); and (4) continued investigation into the interplay between Lp(a) and novel pathways (inflammation, coagulation, etc.) to identify combination therapies that might further mitigate risk.
In conclusion, this systematic review underscores that lipoprotein(a) is a critical factor in premature cardiovascular disease, and it should no longer be regarded as an obscure or “untreatable” risk marker. Instead, it is a measurable, significant risk factor that we can identify early and, with emerging therapies, will likely be able to treat proactively. Through heightened awareness and intervention, the devastating early heart attacks and strokes experienced by some high-Lp(a) patients could become increasingly preventable in the near future.
5. Conclusions
Elevated Lp(a) is a prevalent, independent risk factor for cardiovascular events in individuals under 40, and its contribution to early-onset ASCVD is now well-established. Young patients with unexplained or disproportionate atherosclerotic disease should be evaluated for high Lp(a), and if present, managed with a more aggressive preventive strategy. With novel Lp(a)-lowering therapies on the horizon, there is optimism that we will soon be able to directly mitigate this risk factor, transforming the outlook for patients predisposed to premature cardiovascular disease. In the meantime, heightened awareness and proactive management of Lp(a) and associated risk factors can help reduce the burden of ASCVD in the young, moving us closer to the goal of preventing “heart attacks in their 30s and 40s” in the next generation.
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