The following are key points to remember from a review of lipoprotein(a) [Lp(a)] and cardiovascular disease (CVD):

1. This extensive review of Lp(a) covers the physiology and pathophysiology, genetic evidence of causality, epidemiology, use and treatment strategies in clinical settings, and future therapies.
2. Lp(a) is a low-density lipoprotein (LDL)-like particle in plasma containing cholesterol, triglycerides, phospholipids, and apolipoprotein B (apoB) as with LDL and remnant lipoproteins. It contains the unique apolipoprotein(a) [apo(a)] of variable length depending on number of kringles, which are repeated protein modules covalently bound to the apoB component of the LDL-like particle.
3. Determinants of Lp(a) levels formed in the plasma are novel. The Lp(a) level is high when the number of kringle IV subtype 2 is low and vice-versa. At high numbers of kringle IV subtype 2, many of the apo(a) molecules formed in the liver are degraded within liver cells, whereas at low numbers of kringle IV subtype 2, the molecules are freely secreted to attach to circulating LDL particles outside of liver cells to form Lp(a).
4. High concentrations (plasma level) of Lp(a) are a causal risk factor for CVD in 20% of the global population. High Lp(a) and LDL cholesterol (LDL-C) lead to atherosclerotic CVD (ASCVD), and high Lp(a) can also lead to aortic valve (AV) stenosis. Concentrations are 17% higher in women than in men after age 50 years, which typically coincides with the age of menopause and why women who have had an Lp(a) prior to menopause should have it repeated after menopause or 5 years after age 50.
5. Lp (a) levels are high at birth, peak at about 5 years of age, and do not change much through one’s lifetime. Lp(a) levels >30 mg/dL have been associated with high risk for first and recurrent ischemic strokes in children and adolescents suggesting screening for Lp(a) would be wise, particularly with high LDL-C and those suspected of having familial hypercholesterolemia.
6. Lp(a) can be an acute phase reactant with levels dropping immediately after myocardial infarction (MI) associated with the role of healing of tissue, followed by an increase that can be three-fold in the following weeks. For this reason, levels of lipids including Lp(a) should be measured immediately upon admission of persons with an acute coronary syndrome or stroke and repeated 1-3 weeks after the events.
7. Theoretically, nmol/L is preferred for reporting Lp(a) concentrations, whereas mg/dL works equally well for clinical purposes. The authors used the Denka measure of concentrations in about 14,000 individuals with both units and observed a close relationship between them (coefficient of determination R^² = 0.996): Lp(a) in nmol/L = 2.18 × Lp(a) in mg/dL – 3.83. CV risk cut points are above 50 mg/dL and 105 nmol/L. Severe high risk of CVD is often considered at Lp(a) concentrations above 90 mg/dL (190 nmol/L), and concentrations of 130–391 mg/dL (280–849 nmol/L) correspond to the CV risk seen in individuals with familial hypercholesterolemia. Typical median examples of plasma Lp(a) measured in mg/dL or in nmol/L vary considerably by ethnicities. Examples in mg/dL: East Asian 10, European 12, Latin American 15, South Asian 18, and African 27 mg/dL.
8. CV events attributable to Lp(a) are mainly after age 50 years. In the Copenhagan studies, the risk of CV morbidity and mortality is primarily for individuals within the top 5% of Lp(a) concentrations, or >90 mg/dL (>190 nmol/L). The percent population at risk for CV events is greatest for MI, AV stenosis, peripheral artery disease, and heart failure (33-25%) and CV death 10%. For the percentage of the population at risk of CV morbidity and mortality for high versus low plasma Lp(a), the risk is anywhere from 1.2 to 3.0 times greater at the top 5%. Examples: MI x3, AV stenosis x3, peripheral vascular disease x2, heart failure x1.7, CV death x1.5, and all-cause death x1.2. The risk of CVD morbidity and mortality increases with high concentrations of Lp(a) in all ethnicities and male and females.
9. Based on this evidence, a 2010 European consensus recommendation suggested that individuals at high CV risk should have plasma Lp(a) measured to evaluate additional risk above risks conferred by other CV risk factors. This advice is now found in lipid guidelines and consensus statements globally. The European guidelines suggested everyone have Lp(a) in 2019, which was then endorsed by guidelines in India, Canada, China, and the United States. Cascade screening in families should also be offered to biological parents, siblings, and children of people with familial hypercholesterolemia, or to individuals with a familial or personal history of premature ASCVD.
10. From an evolutionary perspective, Lp(a) creates a survival advantage in mammals. There is a homology between apo(a) and plasminogen indicating a role in fibrinolysis. Inhibition of fibrinolysis leads to better wound healing, e.g. during childbirth and trauma where Lp(a) attaches to sites of arterial injury and fibrin accumulation and could deliver cholesterol for tissue repair and wound healing. In contrast, Lp(a) particles can deliver cholesterol to help form and enlarge arterial plaques, and via kringle structures attach to fibrin in the thrombus and inhibit plasmin-driven fibrinolysis leading to thrombus growth, and increase in CVD and CV events.
11. Lp(a) concentrations are >90% genetically determined suggesting the variation within the LPA gene coding for kringle IV subtype 2 number of repeats is probably the genetic variant that explains the largest variation in a potential disease-causing factor in the entire genome. In addition, many single nucleotide polymorphisms (SNPs) in and around the LPA locus can explain a large variation in plasma Lp(a) concentrations, including for people with the same number of kringle IV subtype 2 number of repeats having lower plasma levels of Lp(a).
12. High Lp(a) concentrations are more common in individuals with both heterozygous familial hypercholesterolemia (HeFH) and homozygous FH (HoFH) than in people without. The amount of LDL-C that is attributable to by plasma Lp(a) levels is not known unless measured directly as Lp(a)-C, but when Lp(a) is very high such as >100 mg/dL, the contribution of cholesterol may increase the LDL-C to levels found in HeFH and create false positive HeFH using Simon Broome and Dutch Lipid Clinic criteria; confusion that would not occur with the point mutations of genetic variants in LDLR, APOB, and PSCK9.
13. Until efficient, safe, and approved Lp(a)-lowering drugs become available, people with high Lp(a) should be considered for the aggressive reduction of other known CV risk factors. Interventions in persons with high Lp(a) for reduction in CV risk include standard guidelines for healthy lifestyle: guideline treatment of blood pressure, diabetes, triglyceride, and remnant cholesterol reduction, and reduction in LDL-C to 55 mg/dL. Agents that do not affect Lp(a) levels but can be used in combination to lower the LDL-C include high dose of high-intensity statins, ezetimibe, and bempedoic acid. For secondary prevention, PCSK9 inhibitors decrease Lp(a) by 25% and LDL apheresis that lowers Lp(a) by 35% is approved and used in Germany and the United States. Niacin reduces Lp(a) by about 25% but because the combination with statins did not reduce CV events in a large clinical trial, it is not used in most countries. No evidence or guidelines advise the use of aspirin for the prevention of ASCVD in the primary prevention setting for people with high Lp(a). However, aspirin should be used in individuals with ASCVD.
14. Five novel treatments are in various stages of clinical trials. The lowering of Lp(a) ranges from 65% to 98% and are given monthly, every 2-4 months or orally in trials. Three are in phase 3 clinical trials for secondary prevention with CVD endpoints. Other drugs being investigated for their effects on lowering high Lp(a) concentrations include oral PCSK9 inhibitors, cholesterol ester transfer protein inhibitors, and gene editing, which are being studied to assess the effect on levels and toxicity/side effects but not yet clinical endpoints. Persons with the lowest levels of Lp(a) have about a 38% increased risk of diabetes, a phenomenon not clearly understood. It is one of the concerns regarding novel treatments being studied in persons with high Lp(a) and high-risk ASCVD.

Clinical Topics: Dyslipidemia, Advanced Lipid Testing, Lipid Metabolism, Nonstatins, Prevention

Keywords: Cholesterol, LDL, Dyslipidemia, Lipoprotein(a)

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