Review Article

Lipoprotein(a): A Novel Risk Factor for Heart Failure and Biomarker of Prognosis? From Pathophysiology to Clinical Practice

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Abstract

Heart failure (HF) is one of the most difficult challenges in cardiology nowadays, constituting a significant global epidemiological, social and economic burden. For many years, there has been a search for new risk factors that predispose to the development of HF and biomarkers that could indicate HF patients with a poorer prognosis. Lipoprotein(a) (Lp[a]) is an estimated risk factor for atherosclerotic cardiovascular disease and aortic valve stenosis, but its causal role in HF has not been clearly defined yet. The results of the few studies regarding the influence of elevated Lp(a) on the development and course of HF are uncertain. However, most authors suggest that elevated Lp(a) increases the risk of HF and may correlate with a higher risk of major adverse cardiovascular events. The aim of this review is to present the current state of knowledge on the importance of the association between Lp(a) levels and HF, from pathophysiology to clinical practice including current management.

Keywords

Lipoprotein(a), heart failure, cardiovascular disease, biomarker, prognosis,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/cfr.2025.46

Disclosure: AM has participated in clinical trials for the treatment of elevated lipoprotein(a) funded by Amgen, Eli Lilly and Novartis. All other authors have no conflicts of interest to declare.

Correspondence: Anna Kowalczys, 1st Department of Cardiology, Faculty of Medicine, Medical University of Gdańsk, Smoluchowskiego 17 St, 80-952 Gdańsk, Poland. E: anna.roz@gumed.edu.pl

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Cardiovascular diseases (CVDs) remain the leading cause of mortality in developed countries.1 Among them, heart failure (HF) affects 1–2% of the population.2 The incidence of HF is steadily increasing, primarily due to population ageing.2 It is estimated that HF occurs in up to 10% of individuals aged over >70 years.2 The main aetiological factors for HF include coronary artery disease (CAD), valvular heart disease and hypertension, which are common in the general population.2 Recent years have seen improvements in diagnostic procedures for HF, optimisation of pharmacological treatment targeting the renin–angiotensin–aldosterone system and sympathetic nervous system, and the introduction of a new group of drugs that have revolutionised the treatment of HF.2,3 Despite these advances, the prognosis for patients with HF remains poor.2,3 Recent data indicate that HF is the most common cause of cardiovascular death in Poland, and exacerbations of HF have become the leading cause of hospitalisation in patients aged >65 years.4

Lipoprotein(a) (Lp[a]) is an LDL-like particle containing an additional protein – apolipoprotein(a) (apo[a]) – encoded by the LPA gene located on chromosome 6.5,6 Approximately 90% of Lp(a) concentration is determined by genetic factors.5,6 Numerous studies conducted on large and diverse populations have documented that Lp(a) concentration linearly correlates with cardiovascular outcomes independently of LDL cholesterol (LDL-C) levels.6,7 Lp(a) is a recognised risk factor for atherosclerotic cardiovascular disease (ASCVD), especially CAD, peripheral artery disease and ischaemic stroke.6–10 It has been shown that ASCVD risk increases by 11% for every 20 mg/dl (~50 nmol/l) increment in Lp(a).8 Furthermore, elevated Lp(a) levels have been confirmed to increase the risk of aortic valve stenosis (AVS) and correlate with the severity of aortic valve calcification.6,11–15

In recent years, reports have also emerged suggesting that Lp(a) may be a risk factor for other CVDs, including hypertension, AF and HF.6,10,16–18 To date, the impact of elevated Lp(a) on the development and course of HF has not been definitively established.10,19 Most authors of the limited studies carried out in this patient group suggest a positive correlation between Lp(a) levels and HF.19 Differences in study results are mainly attributed to heterogeneity of HF populations studied. It should also be noted that available prospective data mostly come from small HF cohorts, reflecting the limited number of studies measuring Lp(a) in this population.6,20,21 Current guidelines recommend measuring Lp(a) at least once in every adult’s lifetime.6,20–24 Moreover, some authors suggest that due to the lipid paradox observed in HF patients, Lp(a) may play a more significant role in cardiovascular risk stratification than baseline lipid profile parameters in this group.1,25–28 Additionally, it has been suggested that Lp(a) correlates with the incidence of major adverse cardiovascular events (MACE), independent of LDL-C levels.29,30 Given these findings, Lp(a) measurement should be incorporated into clinical practice, especially since significantly elevated levels (>50 mg/dl, ~125 nmol/l) are found in up to 20% of Europeans.6,20,21,31,32

The aim of this review is to summarise current knowledge on the association between Lp(a) levels and HF, the significance of elevated Lp(a) as a risk factor for HF development and adverse HF outcomes, and to present current management options for patients with HF and elevated Lp(a), focusing particularly on available and emerging therapies targeting Lp(a) reduction that may improve prognosis in this population.

Lp(a) as a Risk Factor for the Development of HF: Pathophysiological and Clinical Perspective

Pathophysiological Point of View

Little is known about the role of Lp(a) in the HF pathophysiology. Several hypotheses may explain the observed associations between Lp(a) and HF from a pathophysiological perspective. Primarily, Lp(a) is a potent pro-inflammatory, pro-atherogenic and pro-thrombotic factor that significantly increases CAD risk, a major cause of ischaemic HF, especially after acute MI (AMI).6,18,33 Elevated Lp(a) also enhances pro-calcific effects, correlating with increased risk of degenerative aortic valve calcification, potentially leading to severe AVS and predisposing to HF.6,18

The possible mechanisms linking elevated Lp(a) levels to HF development are summarised in Figure 1. Although AF with rapid ventricular response can cause tachycardia-induced cardiomyopathy, the relationship between AF and HF in patients with elevated Lp(a) remains unclear, with some authors suggesting a negative correlation.34,35 Recent hypotheses propose that Lp(a) may directly impair endothelial and vascular smooth muscle function, increasing arterial stiffness and hypertension risk, an important HF risk factor, particularly for HF with preserved ejection fraction (HFpEF).19,36–39 However, Agarwala et al. did not confirm a causal link between Lp(a) and arterial stiffness as a mechanism leading to HF.40 Despite these mechanisms, recent efforts increasingly focus on demonstrating a direct link between Lp(a) and HF development.41,42

Figure 1: Possible Causal Mechanisms Linking Elevated Lipoprotein(a) Levels to Heart Failure Development

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Lp(a) acts as a pro-inflammatory agent, with attached oxidised phospholipids (OxPL) activating inflammatory cells to produce reactive oxygen species, increasing tumour growth factor-β levels and stimulating fibroblasts via long noncoding RNA activation, leading to direct myocardial damage through promotion of interstitial myocardial fibrosis (IMF).43,44 IMF is a significant risk factor for adverse LV remodelling and HF development, especially HFpEF.45,46 Chehab et al. investigated the association between Lp(a) levels and IMF using cardiac magnetic resonance T1 mapping and late gadolinium enhancement in 2,040 patients.42 They found a significant association between elevated Lp(a) (cutoffs 30 and 50 mg/dl) and greater, diffuse IMF, independent of CAD (including prior AMI) or AVS, which can also lead to LV remodelling.42 Additionally, significant left atrial enlargement and dysfunction were observed in patients with Lp(a) >30 mg/dl.42 The authors suggested that early detection of fibrosis by cardiac magnetic resonance combined with elevated Lp(a) may aid HF risk stratification and support the implementation of effective preventive and therapeutic strategies.42,46

Clinical Point of View

Many risk factors for HF development exist, but ongoing research seeks new markers that will be useful in clinical practice. Early identification of high-risk patients would enable timely preventive and therapeutic interventions to prevent HF onset, delay its progression, and/or mitigate its severity. One of the key unresolved questions is the identification of biomarkers that could prove useful in stratifying risk for HF development.47 According to the current European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines for the management of dyslipidaemias, as well as ESC and American Heart Association guidelines on prevention and the recent EAS consensus statement, Lp(a) represents a significant cardiovascular risk modifier warranting consideration beyond risk estimation based on the SCORE2 and SCORE2-OP algorithms.1,6,22,23,48

Given that CAD constitutes a primary aetiological factor for HF, measuring Lp(a) levels may help identify a subgroup of patients particularly vulnerable to its development. For years, the relationship between Lp(a) and HF risk and progression has been investigated. Literature data are scarce and inconclusive, but most authors suggest that patients with elevated Lp(a) have a significantly higher HF risk, especially those with a family history of CVD.16,18,19,49 One large analysis showed that a 20 mg/dl increase in Lp(a) concentration is associated with a 5% increase in HF risk.50

Kamstrup et al. conducted one of the largest Mendelian randomisation studies involving 98,097 patients from two large Danish cohorts (Copenhagen City Heart study and Copenhagen General Population study) to assess the relationship between Lp(a) levels and HF risk.18 The study confirmed a causal association between elevated Lp(a) levels, corresponding LPA risk genotypes and HF risk. The correlation weakened after excluding patients with prior AMI and AVS, suggesting that in most patients, the Lp(a)–HF link is mediated through AMI and AVS, which are major aetiopathogenic factors for HF development. Similar findings were reported by Singh et al. in a meta-analysis of Mendelian randomisation studies, confirming that increased Lp(a) levels are associated with higher HF risk.33 Wang et al. confirmed the association only between elevated Lp(a) and increased risk of CAD, aortic aneurysm, and large artery ischaemic stroke.10

In patients with established CAD, Lp(a) levels positively correlated with the frequency of cardiovascular complications.51,52 In the ongoing 5-year ELITE study, Shrader et al. demonstrated that elevated Lp(a) levels are associated with an increased risk of the composite endpoint, including CAD, stroke, HF, peripheral arterial disease, carotid stenosis and AF, independent of other cardiovascular risk factors.53 Conversely, in a study examining the interaction between Lp(a), LDL-C and polygenic risk score in CVD involving 346,751 participants from the UK Biobank, Liu et al. reported an inverse correlation between Lp(a) levels and AF or HF.54

Dai et al. demonstrated that elevated Lp(a) (≥32 mg/dl) in AMI patients is an independent predictor of MACE, including cardiac death, nonfatal AMI and HF readmission, during long-term follow-up.51 Wu et al. observed that patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention with high Lp(a) levels developed congestive HF significantly more often than those with low Lp(a).55 In the ARIC study, Agarwala et al. confirmed a statistically significant association between Lp(a) levels and increased risk of incident HF hospitalisation over 23.4 years of follow-up; however, the correlation lost significance after excluding patients with prior MI.40 Recently, Zhang et al. confirmed that in patients with elevated Lp(a) following AMI and concomitant HF with HFpEF undergoing percutaneous coronary intervention, there is an increased incidence of MACE, rehospitalisation due to worsening HF, nonfatal recurrent MI and subsequent revascularisation.56

Data on the association between Lp(a) and non-ischaemic, non-valvular HF have been lacking until recent reports suggested a significant impact of Lp(a) on HF development in these patients as well.16,57 Wang et al. suggested that elevated Lp(a), Lp(a) polygenic risk score and family history of CVD significantly increase HF incidence, which is highest when these factors coexist.16 Wang et al. confirmed a positive correlation between Lp(a) levels and left ventricular (LV) ejection fraction (LVEF) in a Chinese hypertensive population without concomitant CAD.57

However, some authors suggest significant differences depending on population/ethnicity.33,49,58 In a 13-year follow-up of 6,809 participants in the MESA study, Steffen et al. found that the positive correlation between Lp(a) and HF, including HFpEF, was statistically significant only in the white population.49 HF risk was significantly higher when Lp(a) cutoffs of 30 and 50 mg/dl were used, and remained significant after excluding patients with prior AMI.49 Differences in Lp(a) levels among populations/ethnicities likely result from genetic polymorphisms of the LPA gene.33 In a recently published pooling analysis of the MESA, Framingham Offspring Study and ARIC cohorts, Nomura et al. showed that among white participants with Lp(a) >50 mg/dl, the total HF risk significantly increases, but only in those with prior MI; no similar association was observed in black patients.59

Some authors also demonstrated that Lp(a) levels correlate with HF progression risk. In the CASABLANCA study, Januzzi et al. evaluated the association between elevated Lp(a), OxPL and symptomatic HF occurrence.41 Among 1,251 patients with ASCVD referred for coronary angiography, those with stage A or B HF were followed for a mean of 3.7 years for HF progression and MACE (HF hospitalisation/cardiovascular death).41 Elevated Lp(a) (≥150 nmol/l) and OxPL levels were associated with significantly higher risk of progression to stage C and D HF and cardiovascular death.41 Notably, OxPL alone did not increase HF event risk, only in combination with Lp(a).41 The risk for incident HF remained significantly elevated after adjusting for CAD and valvular disease presence.41 The authors suggested that Lp(a) and OxPL may exert a direct detrimental effect on the myocardium.41

Due to the limited number of studies, data on Lp(a) correlation with HF subtypes based on ejection fraction – HF with reduced ejection fraction (HFrEF), mildly reduced EF and HFpEF – are lacking. Wu et al. retrospectively evaluated 920 patients divided into two groups by Lp(a) levels (<30 and >30 mg/dl).52 Elevated Lp(a) correlated with HFrEF development, increasing its risk by approximately 17%. In an adjusted model, a 10 mg/dl increase in baseline Lp(a) was associated with an 85% higher risk of HFrEF.52 Moreover, increased Lp(a) at baseline was associated with increased N-terminal pro-brain natriuretic peptide level and decreased LVEF fraction at follow-up.52 The Lp(a)-HF association was more pronounced in men, patients with diabetes or CAD, and less evident in those treated with β-blockers, warranting further study.52 These findings differ significantly from those of Steffen et al., who found no association between Lp(a) levels and HFrEF.49

It should be emphasised that no definitive Lp(a) threshold for significantly increased HF risk has been established. Some studies used cutoffs >30 mg/dl, others >50 or even >70 mg/dl. Most authors agree that higher Lp(a) levels correspond to higher HF risk, but the exact threshold remains undefined.18,21,41 It has been suggested that HF risk increases at higher Lp(a) concentrations than those associated with AVS or AMI risk.6 Although risk increases continuously, establishing an Lp(a) threshold is clinically important for guiding therapeutic interventions aimed at reducing HF incidence and progression.21,41 Routine Lp(a) measurement may improve HF risk prediction and facilitate implementation of primary prevention strategies.

Lp(a) as an Adverse Prognostic Biomarker in Heart Failure

Cardiovascular risk stratification is a crucial component of managing patients with HF, especially in advanced stages of the disease. For many years, new risk factors and biomarkers with significant prognostic value in HF have been sought. Per updated ESC guidelines, LDL levels >50 mg/dl (105 nmol/l) should be regarded as a significant cardiovascular risk factor in all adults, particularly with higher baseline Lp(a).22,60,61 Taking into account the results of available studies, the authors of the guidelines concluded that high Lp(a) levels may correlate with an increased risk of HF, although to a lesser extent than AMI or AVS.22

It is important to emphasise that currently used risk stratification scales for HF patients do not include Lp(a) levels, even though ASCVD is a major aetiological factor. Most authors suggest that in patients burdened with CVD, elevated Lp(a) levels are associated with an increased risk of MACE.6,20 However, literature data regarding the relationship between Lp(a) levels and HF-related outcomes are limited and inconclusive.6,20,62 So far, only a few studies have been published regarding the association between Lp(a) and prognosis within specific HF subgroups classified by aetiology and LVEF.29,36,63,64 Most authors suggest that elevated Lp(a) significantly increases the risk of MACE in patients with HF, especially ischaemic HF and those with CAD with LV systolic dysfunction.29,36,63,65

Li et al., in an observational retrospective study involving 362 patients with ischaemic HFrEF (LVEF <40%), evaluated the impact of baseline serum Lp(a) and high-sensitivity C-reactive protein (Hs-CRP) levels on prognosis.29 After 12 months of follow-up, patients with Lp(a) ≥30 mg/dl had a significantly higher risk of the composite endpoint – cardiovascular death and rehospitalisation due to HF – compared with those with Lp(a) <30 mg/dl.29 Notably, in patients with elevated Lp(a) and Hs-CRP >3 mg/dl, not only was the risk of the composite endpoint increased, but also cardiovascular mortality and HF rehospitalisation, suggesting that systemic inflammation further amplifies MACE risk in this group.29

These findings partially align with those of Zhang et al., who studied the MESA population and suggested that Hs-CRP is a significant modifier of cardiovascular risk associated with elevated Lp(a).65 Nevertheless, Zhang et al. demonstrated that over long-term observation (median 13.6 years), ASCVD risk related to Lp(a) was observed only in the presence of elevated Hs-CRP, indicating that individuals with high Lp(a) and confirmed inflammation require more intensive surveillance and management of ASCVD risk factors.65 Further research is necessary to elucidate the prognostic significance of the interplay between Lp(a) and baseline systemic inflammation (Hs-CRP) in HF patients, with particular attention to the aetiological factors leading to HF development.

Yan et al. showed that in a Chinese population with chronic ischaemic HF, elevated Lp(a) levels (>20.6 mg/dl) correlated with an increased frequency of HF exacerbations during a median follow-up of 186 days.63 Similar conclusions were drawn by Shitara et al., who found that in patients with CAD and reduced LVEF (<50%), elevated Lp(a) levels (mean >21.6 mg/dl) positively correlated over a 5-year follow-up with the composite endpoint of all-cause mortality and rehospitalisation due to ACS or HF.36 The higher the Lp(a) values, the greater the risk of the composite endpoint. The authors suggested that Lp(a) may constitute a valuable biomarker for risk stratification in patients with CAD and LV dysfunction.

Recently, Yadalam et al. revealed that elevated Lp(a) levels ≥30 mg/dl independently predict the risk of CV death or HF hospitalisation in patients with HF (in majority ischaemic, with LVEF ≤40%) during a median follow-up time of 4.3 years.66 When compared with participants with Lp(a) <30 mg/dl after multivariable adjustment, those with Lp(a) 30–49 mg/dl and Lp(a) ≥50 mg/dl had a significantly higher risk of primary outcome. The observed association weakened over time and, although stronger in individuals with ischaemic HF compared with those with non-ischaemic HF, did not reach statistical significance after adjustment for multiple hypothesis testing.

Zhang et al. demonstrated that in ischaemic HF patients, elevated Lp(a) independently increased the risk of MACE, including all-cause mortality, non-fatal MI and any revascularisation.64 The association between Lp(a) and MACE was particularly pronounced in obese patients. Steffen et al. found that in HFpEF patients, elevated Lp(a) correlated with the frequency of HF-related events.49 Data on the relationship between Lp(a) and prognosis in HF with mildly reduced EF patients remain scarce.

Further randomised studies are needed to determine the prognostic value of Lp(a) in HF patients, considering the heterogeneity of this population. The results will undoubtedly contribute not only to improved risk stratification, but also to the individualisation of therapeutic management.

Potential Clinical Implications of Lp(a) Measurement in Heart Failure

Lp(a) measurement should be considered at least once in a lifetime for all adults to identify those with markedly elevated levels (>180 mg/dl or 430 nmol/l), as well as in cases of premature CVD death in family members or for risk reclassification in patients with moderate-to-borderline high risk.6,22,67 This undoubtedly applies to HF patients as well; although Lp(a) is not yet incorporated into risk assessment scales for HF, it should be routinely measured in all HF patients due to its significant clinical implications.2,6

Primarily, assessing baseline Lp(a) values may improve risk stratification for MACE in these patients, especially regarding HF exacerbations and cardiovascular mortality.29 Moreover, most authors agree that HF patients with elevated Lp(a) (>30 mg/dl) require monitoring and comprehensive management, particularly regarding effective control of common cardiovascular risk factors and optimal treatment of the underlying disease according to current guideline-directed medical therapy.6,20,21 HF represents a high-risk condition for future ASCVD events, necessitating prompt optimisation of therapy in this population.9

For all patients with HFrEF, treatment should be based on the four pillars of pharmacotherapy that improve prognosis: angiotensin-converting enzyme inhibitors or angiotensin receptor/neprilysin inhibitors, b-blockers, mineralocorticoid receptor antagonists and sodium-glucose cotransporter 2 inhibitors.2,3,68 For HFpEF patients, symptomatic treatment and sodium–glucose cotransporter 2 inhibitors, the only class shown to improve prognosis in this group, are recommended.3 Interestingly, recent studies suggest aspirin may be effective in reducing cardiovascular events in patients with elevated Lp(a), although further research is required.69 Additionally, comorbidities that may increase Lp(a) levels, especially chronic kidney disease and thyroid disorders, should be intensively treated in all HF patients.6,20 It is worth noting that low Lp(a) levels may increase the risk of developing diabetes, which requires further investigation.6,20 Intensification of treatment in high-risk groups may reduce the incidence of MACE.6,20

To date, none of the first-line HF medications, including sodium–glucose cotransporter 2 inhibitors, have been shown to reduce Lp(a) levels.6,70 Some authors suggest that in ischaemic HFrEF patients with high Lp(a) and elevated Hs-CRP, proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor therapy may reduce cardiovascular risk.29,71 In the near future, patients with significantly elevated Lp(a), ischaemic-HF and non-ischaemic HF with multiple cardiovascular risk factors may benefit from pharmacological therapies specifically targeting Lp(a) reduction.

In patients with ASCVD, Lp(a)-lowering therapy is considered at levels >60 mg/dl, and such an approach has been proposed in the algorithm below.6,7 The proposed treatment algorithm for patients with elevated Lp(a) levels and HF is summarised in Figure 2. However, no definitive Lp(a) cutoff for initiating treatment in non-ischaemic HF patients has been established due to insufficient evidence.

Figure 2: Proposed Treatment Algorithm for Patients with Elevated Lipoprotein(a) Levels and Heart Failure

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Interpretation of results should consider ethnic variability of Lp(a) levels, with the lowest values observed in the Chinese population and highest in black individuals.6,33,60,72 Additionally, challenges exist in precise unit conversion.6 Current guidelines recommend Lp(a) measurement using isoform-insensitive assays reporting particle number in nmol/l, which enhances cardiovascular risk stratification efficacy.6,20 Due to the heterogeneity of HF populations, further randomised prospective clinical trials are needed to evaluate the benefits of Lp(a) reduction in ischaemic and non-ischaemic HF.

Treatment Options Targeted at Reducing Lp(a) in Patients with HF and Elevated Lp(a): Present and Future

Currently, there is no registered pharmacotherapy reducing Lp(a) concentration.6,22–24 An available treatment option is lipoprotein apheresis based on the mechanical removal of excess Lp(a) from the blood dedicated for those with high Lp(a) >60 mg/dl and progressive ASCVD.6,7,22–24 Early optimisation of cardiovascular risk factors and LDL-C control appears crucial when Lp(a)-targeted pharmacotherapy is unavailable; the latest ESC/EAS update proposes using an Lp(a) risk–benefit algorithm to identify high-risk patients for MI or stroke.23,24

However, several clinical trials are currently ongoing on the possibility of using new drugs in therapy aimed at reducing Lp(a) levels. Unfortunately, most studies that assessed the effectiveness of pharmacological treatment in reducing elevated Lp(a) levels do not include patients with HF, especially those with advanced stages.

Statins are recommended per ESC guidelines for high-cardiovascular-risk patients and those with established CVD, particularly post-MI or ACS, to prevent or delay HF onset and hospitalisations.2,3,73 However, current ESC guidelines for the diagnosis and treatment of acute and chronic HF do not recommend routine statin use in HF patients without other indications, as statin therapy in HFrEF has shown no benefit and may even increase Lp(a) levels – although, a large meta-analysis by de Boer et al. indicates statins exert no significant impact on Lp(a).2,3,6,22,74

Although PCSK9 inhibitors can decrease Lp(a) level on average by 27%, which can possibly translate into cardiovascular risk reduction, they are not registered for hyper-Lp(a) treatment.75,76 Gaudet et al., analysing pooled data from three double-blind Phase II studies, found that alirocumab 150 mg every 2 weeks for 8–12 weeks resulted in a 30.3% reduction in Lp(a) from baseline versus placebo in hypercholesterolaemic patients.77 Similarly, Raal et al., in a pooled analysis of 1,359 patients from four Phase II trials, confirmed significant Lp(a) reduction with evolocumab.78 Considered mechanisms of Lp(a) decreasing via inhibition of PCSK9 include lowering of Lp(a) synthesis, increased Lp(a) removal and reduced apo(a) accessibility.79

Some researchers have hypothesised that PCSK9 inhibitors may be beneficial in the group of patients with ischaemic HFrEF. They assume that slowing down the progression of the initial disease will translate into a reduction in the concentration of high-sensitivity troponin T, a marker of heart muscle cell damage and atherosclerosis progression. Bayes-Genis et al. designed a study, EVO-HF trial, where guideline-directed medical therapy with or without evolocumab was compared in a group of 39 patients with HFrEF and stable CAD.80 Interestingly, the authors did not note any significant changes in high-sensitivity troponin T level in either group within the year of observation.

Evolocumab efficacy in Lp(a) lowering was investigated in the FOURIER trial.81 This randomised, double-blind, placebo-controlled clinical trial included 27,564 patients with established ASCVD and LDL-C ≥70 mg/dl (1.8 mmol/l) or a non-HDL cholesterol concentration ≥100 mg/dl (2.6 mmol/l). One of the exclusion criteria was New York Heart Association (NYHA) class III or IV, or last known LVEF <30%. At 48 weeks of treatment, the authors noted significant reduction of Lp(a) concentration, with a median of 26.9%.

The FOURIER OLE trial was a continuation of the FOURIER trial, which included 6,635 patients.82 The data demonstrated that evolocumab is effective in long-term adverse cardiovascular events reduction.

Another PCSK9, alirocumab, was tested in the ODYSSEY OUTCOMES trial, which enrolled almost 19,000 participants with ACS on a statin at the maximal tolerated dose in the last 12 months preceding the start of the trial.83 Nevertheless, the exclusion criteria were NYHA class III or IV HF or LVEF <25%. Patients were administered alirocumab in 2-week intervals. The trial showed a reduction of the ischaemic cardiovascular events in the alirocumab arm. In addition, the Lp(a) level decrease was noted in the intervention group.

White et al. evaluated outcomes in ODYSSEY OUTCOMES patients with versus without a history of HF randomised to the alirocumab or a placebo.84 Alirocumab reduced MACE in patients without a history of HF, but not in patients with a history of HF, and did not reduce hospitalisations for HF in either group. Nevertheless, it should be emphasised that data on timing of diagnosis, LVEF or NYHA were not collected. They concluded that patients with a history of HF do not appear to benefit from PCSK9 inhibition after ACS.

Updated ESC/EAS guidelines emphasise novel pharmacological approaches targeting Lp(a), currently under investigation in clinical trials.22,23 Some of the most promising drugs targeting Lp(a) are small interfering RNA (siRNA) and antisense oligonucleotides. Lepodisiran is an siRNA-lowering Lp(a). Its effectiveness was assessed by Nissen et al. in a randomised trial (NCT05565742), where 320 patients with Lp(a) >175 nmol/l were administered lepodisiran and a placebo in several pathways.85 The injections were given at baseline and after 180 days. The primary endpoint was percentage change of Lp(a) concentration between day 60 and day 180. The authors noted a change of –40.8 percentage points compared with the baseline. The data were time-averaged and adjusted for the placebo. Adverse events related to local reactions were observed after drug administration with a frequency of 12%.

Phase II of the OCEAN(a)-DOSE trial (NCT04270760) assessed the effectiveness of another siRNA-reducing Lp(a), olpasiran, in a group of 281 patients with established ASCVD and Lp(a) concentration >150 nmol/l.86 Olpasiran at the dose of 75 or 225 mg administered every 12 weeks reduced circulating Lp(a) level by >95%. Mostly observed adverse events were site reactions after olpasiran injection. In addition, olpasiran has the potential for prolonged Lp(a) concentration lowering. Sustained Lp(a) level reduction of 40–50% was observed a year after the last dose of olpasiran in the group of patients who received ≥75 mg doses every 12 weeks.

Zerlasiran is another Lp(a) targeting siRNA investigated in clinical trials. The most recent data revealed its effectiveness in time-averaged Lp(a) level lowering. The research group (NCT05537571) consisted of 180 participants. Inclusion criteria were hyper-Lp(a) ≥125 nmol/l and stable ASCVD. During 36 weeks of treatment, a >80% reduction in Lp(a) concentration was noted. Adverse events were mostly local reactions to the drug injection.87

Inclisiran is also an siRNA with an impact on Lp(a) concentration. Further ORION trials revealed inclisiran-related Lp(a) lowering; however, the observed data were ambiguous.88 Several clinical trials investigating inclisiran are currently active and recruiting participants, which may provide additional data on the effects of this drug in the context of Lp(a).

Pelacarsen is an antisense oligonucleotide directed to hepatocytes with Lp(a)-lowering potential. It has been investigated in a Phase IIB clinical trial (NCT03070782) within a group of 286 patients with established ASCVD and Lp(a) ≥150 nmol/l.89 Researchers reported an 80% reduction of Lp(a) concentration with a dose of 80 mg every week regimen compared with a placebo.

Another molecule, muvalaplin, presents a different Lp(a) reduction approach based on the blocking of the apo(a)–apo B100 interaction. A Phase II trial (NCT05563246) included 233 patients with Lp(a) concentration ≥175 nmol/l with ASCVD, diabetes or familial hypercholesterolaemia. Muvalaplin led up to a dose-dependent reduction of Lp(a). Adverse events noted in at least 5% of patients were diarrhoea, nausea, influenza, back pain, myalgia, uterine leiomyoma and anaemia.90

In summary, due to the lack of data on the efficacy and benefits of Lp(a) treatment in HF patients, the possibility of using new drugs targeting Lp(a) requires further clinical trials.

Conclusion

According to current recommendations, Lp(a) should be routinely measured at least once in a lifetime in all patients, including those with HF.6,28,31,32 Lp(a) measurements may be useful in identifying HF patients at high risk of cardiovascular complications. Patients with significantly elevated Lp(a) levels should undergo regular monitoring, intensive control of risk factors, optimisation of treatment of the underlying disease and comorbidities, and assessment of indications for treatment aimed at reducing Lp(a).6,28,31,32 Due to the scarce and ambiguous results of available analyses, there is a need to conduct large studies on the possibility of using Lp(a) as a biomarker of unfavourable prognosis in HF.

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