Even after undergoing optimal medical treatment in line with the latest guidelines, individuals who survive an acute myocardial infarction (AMI) continue to face a less-than-favorable prognosis globally [1, 2]. Consequently, identifying valid residual risk indicators for major adverse cardiac events (MACEs) following AMI is paramount [3]. Indeed, poorly controlled dyslipidemia has been highlighted among the primary drivers of subsequent MACEs since it is significantly influenced by the accumulation of not only low-density lipoprotein (LDL) cholesterol but also other cholesterol-rich apolipoproteins within the vessel wall, such as lipoprotein(a) (Lp(a)) [4, 5].

Lp(a) possesses a core composition similar to that of LDL, containing approximately 30% to 46% cholesterol and oxidized phospholipids, which promotes cholesterol deposition in coronary walls, triggers inflammatory responses, and enhances thrombogenic potential [6]. Recent studies have confirmed that elevated Lp(a) levels are associated with increased risks and adverse coronary artery disease outcomes [7, 8], which remains readily comprehensible for the established correlations of Lp(a) with in-stent restenosis [9], accelerated progression of atherosclerotic plaques, and more severe coronary calcification [10, 11]. Moreover, higher Lp(a) levels have also been linked to other various cardiovascular disorders, such as aortic valve calcification [12] and left ventricular hypertrophy [13]. Notably, as demonstrated in a previous meta-analysis, elevated Lp(a) levels were associated with an increased prevalence of MACEs among individuals with coronary heart disease [14] and higher rates of all-cause and cardiac mortality in the general population [15]. More importantly, Bittner et al. [16] found that reductions in the baseline Lp(a) level could predict the risk of MACEs after recent acute coronary syndrome. However, despite these findings, the clinical significance of Lp(a) in the prognosis of AMI remains controversial. Relevant studies have reported inconsistent results [17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39]; some concluded that elevated Lp(a) levels are associated with an increased risk of MACEs following AMI, whereas others found no significant association between the two.

Given the potential of Lp(a) as a modifiable risk factor, this meta-analysis aimed to synthesize existing cohort studies concerning the relationship between baseline Lp(a) levels and the subsequent risk of MACEs in the AMI population. The objective was to provide a comprehensive understanding of the role of serum Lp(a) levels in AMI prognosis, evaluate its potential as a prognostic marker, and lay the foundation for further validation regarding any underlying mechanisms.

The current review was reported per the PRISMA guidelines [40] (PROSPERO: CRD42024511985).

In the current systematic review, we comprehensively analyzed the association between Lp(a) and the risk of MACEs after AMI. Our findings firstly indicated that higher Lp(a) levels correlated with an increased incidence of MACEs. Further, among subgroup analyses, significant associations between elevated Lp(a) and MACE prevalence among female individuals with DM or hypertension were observed; these links were not observed in the remaining subgroups. In addition, elevated Lp(a) was more seemingly related to long-term rather than short-term MACE occurrences. Altogether, these findings are likely more applicable to female populations with coincident DM or hypertension and more suitable to evaluate the prolonged prognosis following AMI.

No prior systematic reviews and meta-analyses have specifically addressed this topic solely relating to populations surviving AMI, despite substantial evidence illustrating the great harms of elevated Lp(a) in the secondary prevention of recurrent cardiovascular events. Willeit et al. [42] pooled seven randomized controlled trials with 29,069 patients in a review and highlighted those high levels of both baseline and on-statin Lp(a) exhibited an independent approximately linear relation with incident cardiovascular disease in the general population receiving lipid-lowering therapy. In addition, Wang et al. [43] performed a systematic review enrolling 17 studies that indicated a similar relationship between Lp(a) and cardiovascular risks for populations with established coronary artery disease. Notably, a large percentage of the population with dyslipidemia could not gain noticeable benefits from statins or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in secondary prevention therapies [42]. However, these might involve one Lp(a)-associated mechanism that requires an absolute reduction in Lp(a) levels for a clinically apparent decrease in cardiac risk, as highlighted by the Mendelian randomization study [44, 45]. In contrast, routine lipid-lowering drugs could not sufficiently eliminate elevated Lp(a) levels. Moreover, a meta-analysis published in 2020 demonstrated that LDL-C content exhibited an apparent association with incident cardiovascular disease only when the Lp(a) cholesterol content was incorporated into its measurement [46]. Notably, the ODYSSEY OUTCOMES trial has recently demonstrated that alirocumab-related MACE reductions might be mediated via decreased Lp(a) levels [47]. These results indirectly indicate the significant increase in Lp(a)-related risk for recurrent MACEs, which aligns with our findings in the current comprehensive meta-analysis among patients surviving AMI.

Regarding the Lp(a) positive relationship with MACEs after AMI, we found that it might be primarily mediated by the increased cardiovascular mortality in relation to elevated Lp(a); these findings conformed to the Emerging Risk Factors Collaboration, which reported that an elevation in Lp(a) of 3.5-fold correlated with an approximately 14% increase in cardiovascular death; meanwhile, no apparent association was presented for the risk of non-vascular mortality [48]. Overall, these analyses strongly demonstrated that Lp(a)-mediated coronary damage is potentially mainly responsible for the worse prognosis after AMI. Some genetic and epidemiological studies have shown that elevated Lp(a) was associated with the prevalence and progression of myocardial infarction [49], atherosclerotic stenosis [50, 51], as well regarding aortic valve calcification [52, 53]; however, certain mechanisms related to these conditions may contribute to the link between higher Lp(a) levels and an augmented risk of cardiovascular events [47]. Briefly, Lp(a) has been implicated in promoting aortic valve sclerosis and calcification [12], which may contribute to developing aortic stenosis and increasing the burden on the cardiovascular system in AMI patients. Additionally, Lp(a) could aggravate left ventricular hypertrophy [13], a common complication of AMI, by promoting inflammation and fibrosis, which might worsen myocardial function and increase the risk of adverse outcomes. Possible pathophysiological mechanisms might explain these observed correlations. The lipotoxic composition of Lp(a) (low-density lipoprotein-like core, etc.) could be transmitted to the injured vessel walls, causing endothelial dysfunction, inflammation, and consequential atherosclerosis [54, 55]. However, some researchers have also elucidated the prothrombotic roles [56] and anti-fibrinolytic functions of Lp(a) [57]. Lp(a) might interfere with plasminogen activity owing to molecular similarity, leading to a deceleration in fibrinolysis and an indirect promotion of thrombosis. A recent study has shown that combining Lp(a) with fibrinogen and hs-CRP can significantly improve the accuracy of cardiovascular risk prediction [58].

Conversely, the connection between Lp(a) and MACEs seems to exist in females and individuals with DM or hypertension. In diabetic patients, the synergistic effect of high blood glucose and elevated Lp(a) may amplify pro-inflammatory and prothrombotic pathways. High blood glucose contributes to increased oxidative stress and endothelial dysfunction, which may enhance the proinflammatory properties of Lp(a) and promote thrombogenesis, further increasing the risk of adverse cardiovascular outcomes [59]. Similarly, high Lp(a) may worsen the effects of elevated blood pressure in hypertensive patients by increasing vascular stiffness and promoting plaque formation in the arteries, thereby exacerbating the progression of cardiovascular disease. In females, the potential hormonal influence on Lp(a) levels should be considered, as postmenopausal women tend to have higher Lp(a) levels, which may increase their risk of cardiovascular events compared to matched male counterparts [60]. These findings made it easy to understand why the effects of Lp(a) on incident MACEs varied in subgroup populations with or without certain risk factors. Notably, the varying prognostic significance of Lp(a) implied that Lp(a) might act differently in promoting cardiovascular events in populations with and without these above-mentioned risk indicators. Hence, heightened emphasis should be placed on Lp(a) within clinical practice owing to its intricate impact on cardiovascular disorders.

Our meta-analysis still possessed some limitations. Firstly, the included studies had diverse cut-off values of Lp(a), definitions of MACEs, and enrolled populations with varying characteristics, potentially leading to evident heterogeneity. Thus, the pooled findings regarding the relationship between Lp(a) and MACE incidents should be interpreted cautiously. Secondly, due to varied Lp(a) cut-off values among included studies, we could not establish a suitable threshold to distinguish elevated Lp(a). Thirdly, all included studies were cohorts, which limited the ability to establish a causal association between Lp(a) and the occurrence of MACEs. Lastly, factors such as variations in in-hospital management across institutions may have potential prognostic implications for populations surviving AMI, which could partly impact the significance of the conclusions drawn in this review.

In conclusion, Lp(a) was positively associated with MACE incidents, which might primarily be mediated by increased cardiovascular death. This finding seems more applicable to evaluating the long-term prognosis after AMI among female individuals with concomitant DM and/or hypertension. Hence, it is imperative to ascertain further whether Lp(a)- lowering treatment could reduce MACEs and ultimately improve the prognosis of patients surviving AMI. Meanwhile, a rationale for popularizing Lp(a) measurements in patients suffering from AMI should be provided.

All data generated can be obtained from this published article and its additional information files.

HRL contributed to literature review, writing, conception and design, acquisition of data, and analysis and interpretation of data. LSW contributed to investigation, data curation, and drafting the manuscript. XH and ZTD contributed to creating figures, tables, and revising the manuscript critically for important intellectual content. CLL and HW contributed to conception, design, acquisition of data, drafting the manuscript. XTH contributed to drafting of the manuscript, analysis and interpretation of data. All authors have revised the manuscript critically for important intellectual content, also read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

This study was supported by the Beijing Hospitals Authority Clinical Medicine Development of Special Funding Support (ZYLX202111, to X Hou), Beijing Hospitals Authority “Ascent Plan” (FDL20190601, to X Hou), Young Elite Scientists Sponsorship Program by CAST (2022QNRC001, to L Wang), National Natural Science Foundation of China (82200433, to L Wang), and Beijing Hospitals Authority Youth Programme (QML20230602, to L Wang).

The authors declare no conflict of interest.