Introduction

What are lipoproteins? 

Lipoproteins are complexes that transport lipids through the bloodstream. They are composed of hydrophobic lipids in the core and polar components, including proteins, organised on the surface.

Types of lipoprotein

There are primarily five types: chylomicrons, HDL, LDL, VLDL, and IDL. HDL is "good" cholesterol; it moves fat away from the arteries to the liver. The body then gets rid of it. LDL is known as "bad" cholesterol. It deposits fat in artery walls. This buildup creates plaque, causes narrowed arteries, then slows blood flow, and raises the risk of heart problems.

What is a lipoprotein(a)?

The particle Lp(a), also called lipoprotein(a), is similar to LDL cholesterol. Aortic valve issues, clotting, heart disease, and stroke are all known to be genetically associated with Lp(a). It is a distinct type of LDL particle. In 1963, Kare Berg discovered Lp(a).¹ Lp(a) is stickier than LDL. This increases the likelihood of causing blood vessel blockages.

What is hyperlipidemia?

Hyperlipidemia is a condition related to lipid metabolism that involves the buildup of lipids in the blood vessels.² 

Is there any interaction between lipoproteins and hyperlipidaemia?

A link exists between these concepts. Lipoproteins carry fats in the blood. High lipid levels mean fats build up in the artery walls, which is called hyperlipidaemia. The primary contributors to hyperlipidaemia are lipoproteins.

The article aims to increase knowledge of lipoprotein(a)'s significance in cardiovascular disease and its hidden risk factor in hyperlipidaemia.

Structure & composition of Lp(a)

LP(a) is structurally similar to LDL cholesterol. Triacylglycerols and cholesterol esters form the core. Phospholipids, cholesterol, and apolipoprotein B-100 particles make up the edge. In LP(a), apolipoprotein(a) and apolipoprotein B-100 are connected by a disulphide bond. Apolipoprotein(a) contains multiple loops of amino acids (proteins).³

However, because it contains an extra distinctive glycoprotein called apolipoprotein(a) (apo(a)), Lp(a) is different from LDL cholesterol.⁴ Like LDL cholesterol, Lp(a) is a spherical, macromolecular lipoprotein complex.⁴ 

Genetic basis & determinants of lp(a) levels

Genetic factors influence the plasma levels of Lp(a). A study by R. Clarke showed LPA gene changes strongly connected to higher Lp(a) blood levels.. These alterations also increase the risk of heart disease. The apolipoprotein(a) component of Lp(a) encodes the LPA gene.⁵ 

There are several apo(a) isoforms of varying sizes due to the KIV-2 size polymorphism, a copy number variation of the LPA gene.⁶ Lp(a) is not significantly impacted by food, exercise, or most lifestyle modifications, in contrast to other blood lipids. Once early childhood is over, levels stay constant. Elevated Lp(a) is associated with early cardiac disease and often runs in families.

Pathophysiological role in cardiovascular disease

Atherogenic potential

Lp(a) may build up directly on artery walls. Lp(a) oxidises more easily than LDL. This causes scavenger receptors to pull Lp(a) into macrophages faster. Macrophages then turn into foam cells. This is the start of atherosclerosis. It's the main way atherosclerosis forms.⁷

Pro-thrombotic effects

The similarity between apo(a) and plasminogen is what gives Lp(a) its thrombogenic characteristics. By competing with plasminogen for binding sites on endothelial cells, Lp(a) limits fibrinolysis and promotes intravascular thrombosis.⁷

Pro-inflammatory actions

There have also been reports of links between Lp(a) and inflammatory cytokines, such as interleukin-6, transforming growth factor-β, tumour necrosis factor-α, and monocyte chemoattractant protein-1. This mechanism is responsible for vascular inflammation.⁷

Clinical evidence linking lp(a) to risk

Association with premature coronary artery disease

Coronary artery disease is a leading heart problem. This disease's usual results include heart attacks, chest discomfort, and, in extreme cases, death.⁸

Lp(a) should be kept below 50 mg/dL, according to health organisations such as the American Heart Association/American College of Cardiology (AHA/ACC) and the European Society of Cardiology (ESC).⁸

Peripheral artery disease and stroke risk increase

Blood flow from the arteries in the arms and legs is blocked by peripheral arterial disease, or PAD. Klarin et al. discovered a significant correlation between Lp(a) changes and PAD in the most current GWAS analysis.⁹

A Danish study that examined a sizable sample of over 50,000 people found that elevated Lp(a) levels were associated with a higher risk of ischaemic stroke.¹⁰

Lp(a): the overlooked risk factor in a healthy lipid profile

High Lp(a) predicts heart disease. This holds true even with low or managed LDL. A study of over 27,000 people showed this. Lp(a) levels more than 50 mg/dL were associated with increased risk of ASCVD conditions. This occurred even though the LDL level was very low. This highlighted the additive and independent risk posed by Lp(a).¹¹

Limitations in current clinical practice

Doctors typically assess heart health using LDL, HDL, and triglyceride blood levels. A test for lipoprotein (a) helps gauge your risk for heart disease. It also identifies the risk of strokes and other blood vessel problems. This test is not usually used as a routine check for lipid profile. Your doctor usually orders an LP(a) blood test if they suspect a high risk for heart problems. It is also ordered if high lipoprotein (a) runs in your family.

Currently, it is not used in clinical practice due to the following reasons:

Not routinely included in standard lipid panels.

• Lack of universal cut-off values for high risk
• Limited awareness among clinicians and patients

Testing & interpretation

People should test for lp(a) if they have

• An early cardiovascular disease family history (before age 55 for men and before age 65 for women)
• Elevated cholesterol or early atherosclerosis that is unexplained, and they have a healthy lifestyle
• Suffered recurrent heart attacks or strokes despite maximally aggressive lipid therapy

Testing measurements & outcomes

• It is measured in nmol/L or mg/dL
• The size of the particle varies from person to person, there is no straight conversion
• According to a number of criteria, >50 mg/dL (about ~125 nmol/L) is regarded as high risk, while >30 mg/dL (about 75 nmol/L) is regarded as elevated
• Risk increases with higher values, especially in conjunction with other cardiovascular risk factors

Management strategies

Lifestyle changes: minimal effect but beneficial for overall lipid control

Diet, exercise, and weight management are types of lifestyle changes that have no direct effect on Lp(a) levels, but they are important to maintain cardiovascular health and control other lipid and metabolic risk factors.

Pharmacologic options

Niacin

High doses of niacin can lower Lp(a) levels. This reduction is typically around 15-40%. Vitamin B3, or niacin, works well for those who already have high levels of Lp(a). Niacin is not a top choice nowadays.¹²

PCSK9 inhibitors

Studies have demonstrated that the PCSK9 monoclonal antibodies, evolocumab and alirocumab, can decrease Lp(a) by as much as 27% on average, respectively. They are very helpful in managing total cardiovascular risk since they also markedly lower LDL cholesterol.¹³

Emerging therapies: antisense oligonucleotides

In phase 2 trials, an antisense oligonucleotide Pelacarsen (apo A generation) has shown a 35–80% reduction in Lp(a) in phase 2 trials. Lp(a) HORIZON is a critical phase 3 trial in progress. Several promising RNA-based therapies, such as olpasiran, lepodisiran, and APO(a)-LRx, showed reductions of up to 94% for lepodisiran and 66–92% for APO(a)-LRx in early clinical trials.¹⁴

Importance of aggressive control of other risk factors

While no proven method exists to lower Lp(a) levels, managing other heart health risks is crucial. It's essential to maintain LDL cholesterol, blood pressure, diabetes, smoking, nutrition, and exercise. This all-around strategy remains the most successful approach.

Future directions

New RNA treatments, including medications like pelacarsen and olpasiran, are in clinical trials. These studies aim to see if lowering Lp(a) can stop aortic valve disease, heart attacks, and strokes. If trials show clear benefits, Lp(a) screening might become routine. This would especially help those with a family history of heart problems, odd events, or ongoing risks. Adding Lp(a) to risk scores could find high-risk people early. This allows for focused prevention and better control of other risk factors. Such steps could improve public health.

Summary

Lipoprotein(a) [Lp(a)] is a genetically determined, LDL-like particle that acts as an independent and often overlooked cardiovascular risk factor. Severe heart events can be prevented by early testing, proper treatment planning, and managing the risk factors. To improve early detection and reduce the total burden of cardiovascular disease, doctors must promote awareness and incorporate Lp(a) into the standard classification of cardiovascular risk factors.