Research in recent years has found evidence that lipoprotein (a) is a risk factor for cardiovascular disease. Linear and independent increase in lipoprotein (a) levels is predictive of cardiovascular disease. Cardiovascular disease includes coronary artery disease, peripheral artery disease, aortic aneurysm, and ischemic stroke.

Lipoprotein (a) is a lipoprotein that circulates in the blood, consisting of apo (a) covalently bound to apoB (apolipoprotein B-100). ApoB is compositionally similar to apoB found in low-density lipoprotein (LDL) cholesterol.

Although that apo (a) is synthesized in the liver, the place where lipoprotein (a) is formed is unknown. Some of the hypotheses are in the hepatocytes, the dice space, or the plasma compartment. Lipoprotein (a) has no physiological function.



Lipoprotein (a) as a Risk Factor for Cardiovascular Disease

In general, there are four categories of lipid disorders in humans, namely:
  1. Increase in low-density lipoprotein / LDL)
  2. Decreased in high-density lipoprotein / HDL)
  3. Increase in triglyceride (TG) levels
  4. Increased levels of lipoprotein (a)

Diet influences LDL, HDL, and TG levels. However, plasma lipoprotein (a) levels are mediated by the LPA gene and are not influenced by diet or other environmental factors.

Until now, the mechanism and regulation of lipoprotein (a) synthesis and degradation are still not known with certainty. The pathophysiology of lipoprotein (a) in cardiovascular disease development is also not fully understood. One theory put forward is that lipoprotein (a) is atherothrombotic or proatherogenic through its structure, which is low-density lipoprotein.

Lipoprotein (a) and LDL are oxidized after passing through blood vessels' walls, making them pro-inflammatory and immunogenic. So they have the same atherogenic risk.

However, lipoprotein (a) is actually more atherogenic than LDL because lipoprotein (a) not only has an atherogenic component of LDL but also apo (a).

The apo (a) structure can be found within blood vessels' walls and mediates the pro-inflammatory and proapoptotic effects. It is known that apoptosis of macrophages is an important component of the fragility of atherosclerotic plaques.

The apo (a) structure is also said to have several additional effects such as:
  • increase the permeability of endothelial cells,
  • increase the expression of the adhesion molecule,
  • increase smooth muscle cell proliferation,
  • increase the entry of monocytes into the blood vessels,
  • formation of macrophage foam cells,
  • increases the release of pro-inflammatory IL-8
  • antifibrinolytic effect.



Lipoprotein (a) Levels

More than 90% of lipoprotein (a) circulating in the body is not influenced by environmental and dietary factors but is related to the LPA gene. Hence lipoprotein (a) levels are linearly associated with cardiovascular disease risk; as lipoprotein (a) levels increase, the risk of cardiovascular disease also increases.

Because genes influence lipoprotein (a) levels, elevated levels of lipoprotein (a) are present at birth and can contribute to the risk of developing cardiovascular disease at an early age. Lipoprotein (a) levels generally did not change significantly from a few months after birth, except for the acute phase response in which lipoprotein levels (a) can increase rapidly.

To date, there is no standard in measuring lipoprotein (a) levels. The World Health Organization recommends measurement in units of nmol / L through assays of measurement. But apart from that, lipoprotein (a) can also be measured by its molecular mass in the form of mg/dL. In general, nmol / L can be converted to mg / dL divided by 2.8.

Also, there is no consensus or standard regarding the limit of lipoprotein (a) levels. According to several meta-analyses, lipoprotein (a) levels> 25 mg / dL are associated with an increased risk of developing cardiovascular disease. However, some studies have found that lipoprotein (a) levels> 30 mg / dL have only a curvilinear association with the occurrence of cardiovascular disease.

Lipoprotein (a) levels differ in each race. African race has the highest levels of lipoprotein (a) (about 60-70% have a lipoprotein (a)> 25mg / dL), followed by South Asian, Caucasian, Hispanic, and East Asian descent. It is estimated that 20-30% of the world's population has elevated levels of lipoprotein (a) (lipoprotein (a)> 25 mg / dL), which is independent of age, sex, or lipid levels.



How to Low Lipoprotein (a) Levels?

Although there is strong evidence that elevated lipoprotein (a) levels are associated with cardiovascular disease risk, there are no clinical trials that prove that reduced lipoprotein levels (a) have clinical utility. Until now, no agent can specifically and effectively reduce levels of lipoprotein (a) without affecting the levels of other lipoproteins. So this hypothesis cannot be tested until a special agent that can reduce lipoprotein (a) is found.

Several studies have concluded that niacin and estrogen can reduce lipoprotein (a) by 30%. Several other agents could lower lipoprotein (a) levels, including:
  • cholesteryl ester transport protein (CETP) inhibitors, 
  • thyroid mimetics, 
  • calcium antagonists, 
  • angiotensin enzyme inhibitors, 
  • PCSK9 inhibitors, and aspirin (81 mg/day), 
  • and mipomersen. 

However, all of these agents also affect other lipoprotein levels and are not specific to lipoprotein (a).
Several studies recently examined the effect of statins on lipoprotein (a) and found that statins can increase lipoprotein (a) levels. So far, the assumption is that statins do not affect lipoprotein (a) levels because LDL receptors have no role in lipoprotein (a) clearance.

However, several studies have found that statins can increase lipoprotein (a) levels by as much as 10-20%. This is what explains why statins are not able to reduce LDL levels in some individuals. In some of these individuals, most cholesterol is found in lipoprotein (a) particles and not in LDL particles. So that statin administration actually increases lipoprotein (a) levels.

Currently, several agents are being developed to reduce levels of lipoprotein (a). Because hepatocytes synthesize apo (a), therapeutic agents that target hepatocytes can lower lipoprotein (a) levels. One of these therapeutic agents is an antisense oligonucleotide (ASO). Via subcutaneous injection, this agent targets hepatocyte cells. ASO inhibits the apo (a) allele, thereby preventing the formation of lipoprotein (a) and decreasing the level of lipoprotein (a).



Recommendation

There is still debate about the role and clinical function of checking lipoprotein (a) levels, so the various current guidelines' recommendations are different.

The European Atherosclerosis Society recommends screening for lipoprotein (a) levels in patients who have:
  • History of premature cardiovascular disease
  • Familial hypercholesterolemia
  • Family history with a history of premature cardiovascular disease or elevated lipoprotein levels (a)
  • Recurrent cardiovascular disease despite statin therapy
  • > 3% risk-10-year risk of fatal cardiovascular disease (based on European guidelines)
  • > 10% risk-10-year fatal/non-fatal congestive heart disease (based on United States guidelines)

In addition, the European Atherosclerosis Society also recommends that target lipoprotein (a) levels be <50 mg / dL and use niacin (1-3 grams/day) to reduce lipoprotein (a) levels. However, both of these recommendations are controversial. There are no consensus on target lipoprotein (a) levels, and all studies regarding niacin as a lipoprotein (a) lowering agent have been retrospective studies.

The Canadian Cardiovascular Society considers lipoprotein (a)> 30 mg / dL a risk factor for cardiovascular disease. It also recommends measuring lipoprotein (a) levels to aid in decision making, especially in patients with a moderate risk of cardiovascular disease, family history of premature coronary artery disease, and young patients who do not meet the criteria for treatment.

British and German guidelines used lipoprotein (a) levels> 60 mg / dL to include patients with elevated levels of isolated lipoprotein (a) or uncontrolled elevations in LDL levels.

The National Lipid Association guidelines from the United States recommend checking lipoprotein (a) levels in individuals at moderate or high risk of cardiovascular disease. However, these guidelines do not provide recommendations regarding target lipoprotein (a) levels or the therapy administered.

Most patients are not aware of the risk of cardiovascular disease associated with lipoprotein (a) levels. As a screening and diagnostic examination, it is better to check the lipoprotein levels (a) in examining the lipid profile for the first time. Because genes influence> 90% of lipoprotein (a) levels, if the lipoprotein (a) levels are normal, the examination of lipoprotein (a) does not need to be repeated. However, if the patient is receiving treatment to lower lipoprotein (a) levels, it is recommended that the test be repeated to assess the therapeutic response.