Levels are predominately (70-90%) genetically determined.4,9,10
Non-genetic causes include:
Menopause due to declining oestrogen levels2
Kidney disease is associated with both an increased risk of vascular disease and an acquired elevation in Lp(a) levels7
Lp(a) in calcific aortic stenosis
Aside from ASCVD, Lp(a) is a risk factor for calcific aortic stenosis (CAVS), the most common form of valvular heart disease in developed countries. Pathophysiologic, epidemiological, and genetic studies over the past two decades have provided strong evidence that Lp(a) is an important mediator of calcific aortic valvular disease (CAVD)11; individuals with elevated Lp(a) are at 3x risk of developing aortic valve stenosis (AVS) vs compared to those with low Lp(a) levels.12
Lp(a)-targeted therapies are needed to address Lp(a)-associated CV disease risk
Currently there are no approved therapies for lowering Lp(a) levels. Observational and mendelian randomisation studies suggest that an absolute Lp(a) lowering of 50–100 mg/dL is needed to effectively lower Lp(a)-associated CV disease risk.13,14 Therapies such as niacin, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and mipomersen show modest reduction of Lp(a) levels by 20-30%, notably these are not licensed for use in targeting elevated Lp(a). Similarly, apheresis leads to a time-average reduction of 30% to 35%. Apheresis is available in the UK but is not standard of care.15
KV, Kringle 5; KIV-1, Kringle 4 type 1; KIV-3 to 10, Kringle 4 types 3 to 10;
ApoB-100, Apolipoprotein B100; NH2, NH2-terminal; COOH, C-terminus
Adapted from Cegla J et al, 2019
The structure of Lp(a)
Lp(a) is an LDL-like particle, with a single apolipoprotein B100 (apoB), covalently linked by a disulphide bond to a single apolipoprotein(a) (apo(a)). The molecular mass of apo(a) can vary between 275 and 800 kDa due to the inheritance of>40 different allelic LPA variants encoding different numbers of kringle IV type 2 repeat sequences in this polypeptide.
The rate of apo(a) synthesis and secretion is inversely related to its molecular mass, and consequently, individuals who produce the lower molecular mass apo(a) isoforms have higher serum Lp(a) levels than those who produce the higher molecular mass isoforms.1
Elevated Lp(a) may drive fast-progressing and vulnerable atherosclerotic plaques
In patients with advanced stable coronary artery disease (CAD), elevated Lp(a) was associated with accelerated progression of the necrotic core.16
Patients with elevated Lp(a) may exhibit a more severe disease presentation, which refers to the complex atherosclerotic lesions that are more difficult to treat.17
In patients with acute coronary syndrome (ACS), elevated Lp(a) drives a higher prevalence of vulnerable plaque characteristics, including thin-cap fibroatheroma.18
Elevated Lp(a) levels are independently associated with plaque progression and vulnerable plaque characteristics.19,20
See the notes section for references.
ACS, acute coronary syndrome; CAD, coronary artery disease; ECs, endothelial cells;
FH, familial hypercholesterolemia; Lp(a), lipoprotein(a); SMCs, smooth muscle cells.
How does elevated Lp(a) affect cardiovascular health (CV)?
- Elevated Lp(a) is independently and causally associated with increased risk of myocardial infarction (MI), peripheral arterial disease (PAD), ischemic stroke (IS), aortic valve stenosis (AVS), and cardiovascular (CV) mortality.10,21,22
- Patients with elevated Lp(a) may exhibit a more severe disease presentation, which refers to complex atherosclerotic lesions that are more difficult to treat.17
- In patients undergoing coronary angiography, elevated Lp(a) levels are associated with a greater rate of significant obstructive disease and three-vessel disease.23
- In patients with ASCVD and elevated Lp(a), circulating inflammatory and vascular dysfunction markers were elevated; Lp(a) amplifies atherothrombotic risk by driving monocyte-mediated tissue factor expression and activation.24
Elevated Lp(a) is independently and causally associated with increased risk of MI, PAD, IS, and CV mortality
By NOT measuring an Lp(a) level, the lifetime risk of a CV event could be substantially underestimated26
Pro-atherogenic
Oxidised phospholipids (OxPLs) on Lp(a) likely contribute to its pro-inflammatory and pro-atherogenic potential, and pro-osteogenic potential in coronary artery vasospasm (CAVS).28,29
- Endothelial cell binding
- Upregulation of adhesion molecules
- Smooth muscle cell proliferation Proteoglycan matrix binding
- Foam cell formation
- Necrotic core formation
- Lesion calcification
Pro-inflammatory
Lp(a) elicits pro-inflammatory responses of vascular and immune cells, which are key initiating steps in atherosclerosis.28,29
- Macrophage Interleukin 8 (IL-8) expression
- Monocyte cytokine release
- Oxidised phospholipids
- Monocyte chemotaxis/ transmigration
- Lp(a) carries Monocyte Chemoattractant Protein-1 (MCP-1)
Prothrombotic
A pro-thrombotic role for Lp(a) has been hypothesised since the discovery of apo(a) sharing extensive homology (75-99%) with the blood clotting protein plasminogen. Potential pro-thrombotic mechanisms of Lp(a) include promotion of platelet aggregation, accelerated coagulation, more resistant fibrin structures and vulnerable plaques.28,29
- Plasminogen activation
- Fibrin degradation
- Endothelial cell Plasminogen activator inhibitor-1 (PAI-1) expression
- Tissue factor pathway inhibitor (TFPI) activity
- Platelet activation
A 2024 study revealed that elevated Lp(a) was associated with a more severe presentation of coronary artery disease (CAD). Awareness of Lp(a) levels in patients with CAD may have implications in their clinical management.17
Patients with CAD suffer with progressive plaque build-up in the walls of coronary blood vessels, which restricts blood flow and may result in serious cardiovascular outcomes such as angina and MI. In the study, it was observed that elevated Lp(a) was associated with a higher proportion of patients with prior CAD, prior interventions on coronary blood vessels, and more diseased blood vessels. These collectively form what is considered a ‘severe’ clinical presentation of CAD, meaning a greater likelihood of adverse clinical outcomes.17
