1. Introduction

Lipoprotein(a), or Lp(a), is a type of lipoprotein particle that carries cholesterol in the blood similar to LDL lipoprotein particles, but with a unique apolipoprotein (a) attached to it. The role of lipoprotein(a) and the severity of infections are intertwined^[1,2]. During an acute-phase response to an infection, the cytokine interleukin 6 (IL-6) activates the LPA gene through IL-6 response elements^[3]. While the basal levels of Lp(a) are genetically determined, during an acute infection, the levels may increase markedly. Lp(a) particles, in turn, induce the expression of inflammatory genes^[4]. Increased Lp(a) levels have been demonstrated in, for example, chronic inflammatory diseases and sepsis^[5-7].

It has also been shown that oxidized phospholipids (oxPLs) on apo(a) mediate numerous atherothrombotic molecular and cellular events leading to atherothrombotic cardiovascular disease^[8]. Interestingly, in transgenic mice (E06-scFv mice), elevated oxPL levels were associated with increased morbidity and shorter survival rates, and levels of interleukin 10, which are known to be anti-inflammatory in action, were suppressed^[9]. These observations support the role of oxPLs as a key mediator in host-derived damage-associated molecular patterns^[10]. While not shown in the context of Lp(a), the above findings may also be associated with elevated Lp(a) levels during infections.

The current Lp(a)-related scientific literature is mainly related to cardiovascular diseases. In contrast, information about the possible role of Lp(a) in infectious diseases is scanty. Therefore, in an attempt to fill this gap in cumulative knowledge, in this perspective article we highlight findings related to Lp(a) in various common infectious diseases, such as acute bacterial sepsis, and in viral diseases such as those caused by SARS-CoV-2, human immunodeficiency virus (HIV), hepatitis viruses, cytomegalovirus, Helicobacter pylori, Chlamydia pneumoniae, and finally in parasitic infections such as malaria and trypanosomiasis. Since infections are considered contributory components in cardiovascular diseases, but the available data based on epidemiological and follow-up studies are conflicting, we also speculate about the possible modulatory role of Lp(a) in the proatherogenic role of infections. Based on data on the above-mentioned infections and Lp(a), we highlight Lp(a)’s role in these common infectious diseases. This perspective article updates the fragmented data available and explores the nexus between infection and Lp(a), also in the context of cardiovascular disease.

2. SARS-CoV-2

In the early phases of the COVID-19 pandemic, measurement of Lp(a) was recommended to determine if it may contribute to, or be a biomarker of, cardiovascular complications of COVID-19^[11]. It has been postulated that Lp(a) may inhibit fibrinolysis and promote proinflammatory and proatherogenic effects^[12,13]. Furthermore, the cytokine storm that occurs with acute COVID-19 infection increases IL-6 and can affect the LPA gene with a resultant increase in Lp(a) level. Table 1 summarizes various studies on COVID-19 patients and the effects of Lp(a) concentrations during infection.

In several studies, Lp(a) levels were shown to be increased during SARS-CoV-2 infection and to have an impact on both the severity of infection and cardiovascular events. This has been shown especially in the heterozygous form of familial hypercholesterolemia^[19]. In one follow-up study, Lp(a) levels remained elevated for a relatively long time following SARS-CoV-2 infection. Based on these and other studies, Lp(a) does not appear to be associated with increased thrombotic events. However, because the study designs differed, a reliable comparison of the results is difficult. Although it can be concluded that Lp(a) levels appear to be informative about the prognosis of significant SARS-CoV-2 infections, monitoring of Lp(a) levels should still be considered part of the treatment protocol for this infection^[13].

Of note, while apo(a) is a specific protein component in Lp(a) particles, apo-A1 and apo-A2 are apolipoprotein components of high-density lipoprotein (HDL) particles. Little, if anything, is known about potential interactions between Lp(a) particles and HDL particles, and therefore they are not discussed here^[20-23].

3. HIV

HIV infection is an independent risk factor for coronary heart disease (CHD), and the infected patients have a two-fold greater risk of developing CVD when compared with people without HIV^[24]. In a recent study, Lp(a) levels were significantly higher (p < 0.01) in HIV-infected individuals (N = 65; 78 nmol/L [39-137 nmol/L]) compared with controls (N = 52; 45.5 nmol/L [18-102.5 nmol/L]^[25]). Of note, in the HIV-positive patients, the Lp(a) levels correlated inversely with coronary endothelial function. The study highlights the need for further research to elucidate Lp(a)’s role in patients with this chronic infectious disease.

Earlier studies also suggested a possible role of Lp(a) in HIV infected patients. Enkhmaa et al.^[26] showed that in patients with HIV infection, allele-specific apo(a) levels were higher in subjects with higher CD4+ T-cell counts or a low plasma HIV RNA viral load. Additionally, they found that allele-specific apo(a) levels were associated with smaller (< 28 K4) atherogenic apo(a) sizes and were higher in patients with CD4+ T-cell counts ≥ 350. It was concluded that HIV-infection reduced allele-specific apo(a) levels and, despite atherogenic small apo(a) sizes, it might contribute to CHD risk among HIV patients with improved infection status. Enkhmaa et al.^[27] also showed that antiretroviral therapy increased Lp(a) levels. Also, in a relatively small study, perinatally HIV-infected children were shown to have elevated Lp(a) levels, which was partly contributed by their ethnic background^[28]. Currently, the Lp(a) related research in HIV is targeted at improving cardiovascular health among HIV infected patients, as the treatments have greatly improved survival and prognosis in HIV-infected individuals^[25,29].

4. Sepsis

Several studies have shown that Lp(a) levels increase during acute sepsis as cytokine interleukin-6 (IL-6) activates the LPA gene through IL-6 response elements^[3]. However, other studies have not supported this observation. The role of Lp(a) as an acute-phase reactant was evaluated in a study measuring plasma Lp(a) levels, apo(a), apo(a) fragments, urinary apo(a), C-reactive protein (CRP) as well as low-density lipoprotein cholesterol (LDL-C) in 9 patients with acute sepsis who were treated in the intensive care unit and four patients with extensive burns^[5]. Both in the sepsis and burn patients, Lp(a) and LDL-C levels declined and closely mirrored the increase in CRP levels. Among five surviving sepsis patients, Lp(a) levels were 5- to 15-fold lower during sepsis compared to 16 to 18 months after sepsis. There were no changes in apo(a) fragment levels or urinary apo(a) during the study period. In this study, it was shown that Lp(a) acts as a negative acute phase reactant in acute sepsis, and that the decline was not due to accelerated fragmentation of Lp(a).

The above finding that Lp(a) acts as a negative acute phase reactant in sepsis is supported by a larger follow-up study of 9,861 hospitalized sepsis patients^[30]. In this larger study, Lp(a) decreased initially but then increased significantly [Lp(a) at baseline = 24.6 ± 16.06; Lp(a) at sepsis-2 years = 8.25 ± 5.17; Lp(a) at more than 2 years = 61.4 ± 40.1; p = 0.0032]. There were also other long-term abnormalities, such as increased levels of total cholesterol, LDL-C, and high-sensitivity CRP, each of which could have contributed to an accelerated CHD after the single septic episode. The authors concluded that there seems to be metabolic reprogramming after sepsis. Metabolic reprogramming is known to occur after systemic infection, as the human body prioritizes eliminating the pathogenic microbe at the expense of disease tolerance^[31]. It has been shown that, during viral infections, metabolic reprogramming enables immune cells to adjust their energy production while attempting to restrict viral invasion^[32]. There does not appear to be detailed knowledge on how Lp(a) could potentially be related to metabolic reprogramming in infections. Table 2 summarizes studies that have reported on the effects of Lp(a) during and after sepsis.

5. Hepatitis

As early as 1996, Geiss et al.^[33] studied 74 hepatitis patients (32, 28, and 14 with hepatitis A, B, and C, respectively) and found that during acute hepatitis, median Lp(a) concentrations in these patients significantly decreased compared with controls (7 vs. 17 mg/dL; p < .0001, Mann-Whitney test). In a subsequent study, Lp(a) was measured in 130 patients (50 with acute viral hepatitis, 30 with chronic active hepatitis, 30 with cirrhosis of the liver, and 20 with fulminant hepatic failure)^[34]. The Lp(a) levels were reduced significantly (p < 0.001) in patients irrespective of theaetiology compared with 50 controls.

Oliveira et al. showed that apo(a) inhibits hepatitis C virus entry through interaction with infectious particles^[35]. This study was carried out with a recombinant virus derived from the JFH1 strain. The authors showed that, by using plasma-derived and recombinant Lp(a) as well as purified recombinant apo(a) variants, apo(a) was able to modify HCV infection, and HCV was specifically inhibited by apo(a) interacting with the infectious particles. In additional experiments, these authors demonstrated that Lp(a) can inhibit HCV infection. Table 3 summarizes studies reporting Lp(a) levels during viral hepatitis.

6. Helicobacter pylori, Chlamydia pneumoniae, Cytomegalovirus, Malaria and Trypanosomiasis

Lp(a) levels have been studied in several other infections known to be associated with increased risk of atherosclerosis. In a study of 470 healthy blood donors and 238 patients with angiographically proven CHD, those who were seropositive for Chlamydia pneumoniae, chlamydial lipopolysaccharide, or cytomegalovirus were found to have Helicobacter pylori infection, and Hoffmeister et al.^[36] evaluated further. Lp(a) levels were not different between healthy blood donors and patients with CHD regarding seropositivity for Chlamydia pneumoniae, cytomegalovirus, or Helicobacter pylori infection. However, this study does not exclude the possibility of short-term elevation in Lp(a) levels during an acute infection. In another study, Lp(a) levels were measured in 111 patients with malaria and in 106 symptomatic controls (defined as malaria-negative febrile patients) in Gabon^[37]. No significant differences were found in Lp(a) levels between these groups, although the levels declined acutely during the infection. Over 20 years ago, it was discovered that apoL1 protects humans against infections by trypanosome subspecies that cause African sleeping sickness (trypanosomiasis)^[38,39]. High levels of apoL1 protect against trypanosomiasis, and although apoL1 is carried mainly in HDL, it is also carried by Lp(a). Black Africans have higher Lp(a) levels, and a possible explanatory reason for it may be the ability of Lp(a) to protect against Trypanosoma brucei gambiense, which is endemic in West and Central Africa^[40].

7. New Lp(a) Lowering Drugs

Several Lp(a) lowering drugs are being studied in clinical trials, including siRNA formulations (olpasiran, zerlasiran, lepodisiran), an antisense oligonucleotide (pelacarsen), and muvalaplin, which is a small molecule oral drug^[41-46]. Currently, these drugs are being studied in clinical trials but are not yet in clinical use.

Antisense oligonucleotide (ASO) and siRNA formulations decrease Lp(a) levels by more than 90%^[47]. ASOs are single-stranded DNA or RNA molecules, typically 15-25 nucleotides in length. They act by binding to complementary RNA sequences, leading to the degradation of target mRNA through RNase H activation or by steric hindrance that prevents translation. For Lp(a), they are designed to reduce apo(a) synthesis by inhibiting apo(a) mRNA^[48]. In contrast, siRNAs are double-stranded RNA molecules about 20-25 nucleotides in length. They function through a process called RNA interference (RNAi), where one strand of the siRNA guides the RNA-induced silencing complex to the target mRNA encoding Lp(a), leading to its cleavage and degradation^[49].

The mechanism of action of muvalaplin is different from the other drugs currently in clinical trials; it inhibits the first step of Lp(a) formation by blocking the apo(a)-apo B100 interaction and therefore results in reduced formation of Lp(a) by the liver^[46]. Inasmuch as Lp(a) is an independent risk factor for both atherosclerotic cardiovascular disease and aortic stenosis, these agents may reduce the risk of both diseases, but this remains to be proven. Whether the marked reduction in Lp(a) achieved with these agents will result in decreased or increased susceptibility to infections, both acute viral infection and sepsis, as well as more chronic viral infections such as HCV, and parasitic infections such as malaria and trypanosomiasis, requires further study.

Lp(a) is known to trigger several inflammatory pathways, including monocyte activation, which induces secretion of several pro-inflammatory markers and upregulation of chemokine receptors, adhesion molecules, transmigration markers, and scavenger receptors^[2,50]. Lp(a) also contributes to endothelial inflammation and causes endothelial dysfunction^[51]. So new drugs designed to decrease atherosclerotic events by lowering Lp(a) may also affect the body’s response to certain infections. This challenging situation – either for better or worse - needs to be studied in placebo-controlled trials targeting a primary decrease in vascular events.

8. Limitations

Unfortunately, Lp(a) is not measured routinely during infections, and only a limited number of studies have reported on Lp(a) levels related to common infections^[2]. In addition, in the majority of these studies, Lp(a) was measured only once, and there are no available follow-up data during and after the infection. New specific Lp(a) lowering drugs are not yet approved for clinical use, so their impact on infection has not yet been studied^[45].

9. Conclusion

The primary focus of research currently is on the importance of Lp(a) as a risk factor for vascular disease^[3]. Less attention has been paid to the fact that Lp(a) plays a role in both the severity of infections and the vascular disease events following infections^[2]. Currently, the most convincing evidence is from retrospective analyses and follow-up studies of patients with SARS-CoV-2 infection, which show that this infection is more severe in those patients with high Lp(a) levels^[1,14,15]. In addition, SARS-CoV-2 infection per se increases Lp(a) levels, and these levels remain high for a prolonged period, acting as a potential risk enhancer for cardiovascular events^[16]. Of particular interest is that apo(a) and Lp(a) can act as inhibitors of HCV infection and are also important for protection against parasitic infections such as malaria and trypanosomiasis. New drugs significantly lower Lp(a) levels, and it is therefore important to know the significance of low Lp(a) levels in terms of infections. Muvalaplin has a different mechanism of action, and it remains to be seen whether Lp(a) drugs with distinct mechanisms are relevant for infections. Muvalaplin inhibits the first step of Lp(a) formation by small molecule interactions with apo(a), but apo(a) continues to be produced, and serum apo(a) levels are not markedly decreased^[46]. When new Lp(a) specific drugs are approved for use in the future, it will be important to also report on infections reported in these placebo-controlled studies that are targeted to decrease vascular events.

Authors contribution

Vuorio A: Writing-original draft, writing-review & editing.

Kovanen PT, Budowle B, Raal FJ: Writing-review & editing.

Conflicts of interest

Alpo Vuorio has received consultancy fees from Amgen and Novartis. Petri T. Kovanen has received consultancy fees, lecture honoraria, and/or travel fees from Amarin, Amgen, Novartis, Raisio Group, and Sanofi. Frederick J. Raal has received research grants, honoraria, or consulting fees for professional input and/or lectures from Sanofi, Regeneron, Amgen, Novartis, and LIB Therapeutics. Bruce Budowle declares no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

None.

Copyright

© The Author(s) 2025.