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Lipoprotein(a), or Lp(a), is an established and genetically determined risk factor for atherosclerosis, coronary artery disease, stroke, thrombosis, and aortic stenosis.[1] Structurally, it is a variant of low-density lipoprotein and features apolipoprotein(a), or apo(a), which is bound to apolipoprotein B-100, or apoB100. These 2 structures are assembled in the hepatocyte cell membranes and are bound by 1 disulfide bridge.[2] The electrophoretic mobility of Lp(a) is typically pre-β but can vary between that of low-density lipoprotein (β) and albumin (pre-α).[3] Plasma concentrations of Lp(a) and the apo(a) isoform are inversely related.[4] The variation in isoforms is induced by the number of kringle IV repeats in the LP(a) gene. The variation in kringle units leads to the variable levels of Lp(a) observed in the general population. In general, individuals with fewer kringle repeats tend to have smaller Lp(a) particles but higher serum levels. In addition, larger isoforms of apo(a) lead to an increased accumulation of its precursor intracellularly within the endoplasmic reticulum.[5] Lp(a) levels >50 mg/dL are associated with an increased risk of cardiovascular diseases.[2] Internationally, there is a general disagreement on screening guidelines. Screening patients for elevated Lp(a) levels could help identify those who need more aggressive lipid therapy and cardiovascular disease risk management. The suggestion has been made that, for younger patients, coronary artery disease could be explained by Lp(a), with or without other risk factors.[6] No specific therapy exists for treating elevated Lp(a). Most generalized screening aims to identify elevated Lp(a) as an existing risk factor, followed by subsequent optimization of overall cardiac health as the primary treatment. While certain medications such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and niacin directly lower Lp(a) levels, there is no Food and Drug Administration (FDA)-approved medication for the treatment of elevated Lp(a). Further research will contribute to the improvement of both screening guidelines and treatment modalities.[7]

Lp(a) is a distinct lipoprotein structurally related to low-density lipoprotein, containing an apoB100 per particle and sharing a similar lipid composition. Lp(a) also includes a carbohydrate-rich protein called apo(a), which is covalently bound to apo B 100 through a disulfide linkage.[2] Apo(a) exhibits significant sequence homology with plasminogen; however, unlike plasminogen, it is not an active protease.[10] Apo(a) contains a high degree of variation in its polypeptide chain length because of a variable number of kringle domains.[8] Plasminogen contains 5 kringle domains, whereas apo(a) contains only kringle types 4 and 5. There are 10 distinct classes of kringle IV-like domains in apo(a) that differ in amino acid sequences. Kringle IV type 1 and kringle IV types 3 to 10 are present as a single copy, whereas kringle IV type 2 exists in varying numbers of repeats (1 to >40). Thus, there are different-sized isoforms of apo(a) classically described as either large, high molecular weight or small, low molecular weight forms.[11] Paradoxically, due to the ease of hepatic production and secretion of the low molecular weight isoforms compared to high molecular weight isoforms, there can be a significant discordance between Lp(a) mass and Lp(a) particle (Lp(a)-P) concentrations. At the same Lp(a) mass, those with low molecular weight isoforms will have a higher Lp(a)-P concentration compared to those with high molecular weight isoforms.[12] Low molecular weight isoforms are believed to be a significant cause of cardiovascular disease compared to high molecular weight isoforms. However, this may be primarily related to their higher Lp(a)-P concentration rather than anything inherent in the particle. Adding to the complexity is the codominant type of inheritance that occurs with Lp(a), with patients frequently having 2 different types of apo(a)-size isoforms expressed differently.[13]

Paradoxically, due to the ease of hepatic production and secretion of the low molecular weight isoforms compared to high molecular weight isoforms, there can be a significant discordance between Lp(a) mass and Lp(a) particle (Lp(a)-P) concentrations. At the same Lp(a) mass, those with low molecular weight isoforms will have a higher Lp(a)-P concentration compared to those with high molecular weight isoforms.[12] Low molecular weight isoforms are believed to be a significant cause of cardiovascular disease compared to high molecular weight isoforms. However, this may be primarily related to their higher Lp(a)-P concentration rather than anything inherent in the particle. Adding to the complexity is the codominant type of inheritance that occurs with Lp(a), with patients frequently having 2 different types of apo(a)-size isoforms expressed differently.[13] According to genetic and epidemiological studies, Lp(a) is considered pro-atherosclerotic, pro-inflammatory, pro-thrombotic, and anti-fibrinolytic.[6] Lp(a) increases the expression of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, thereby promoting the adhesion of monocytes to the endothelium and initiating atherosclerotic plaque formation.[14] Lp(a) exhibits a higher affinity for the vascular wall, proteoglycans, and fibronectin on the endothelial cell surface compared to low-density lipoprotein cholesterol and other apo B-containing lipoproteins. This leads to the accumulation of Lp(a) in the arterial intima, contributing to the development of atherosclerotic lesions. Macrophages can take up Lp(a), leading to the formation of foam cells, which is a hallmark of early atherosclerosis.[15] Because of its structure, Lp(a) leads to reduced fibrinolysis. Specifically, apo(a) carries a structure similar to tissue plasminogen activator and plasminogen. This similarity allows it to compete with plasminogen for its specific binding site, thereby interfering with its function and leading to reduced fibrinolysis.[16] Thrombogenesis is also stimulated by Lp(a) as it leads to increased plasminogen activator inhibitor-1. The potential benefits of Lp(a) for the human body remain uncertain.[17] A theory suggests that Lp(a) has a role in the healing of wounds. However, individuals with significantly lower Lp(a) levels do not appear to have long-term health risks.[18]

Lp(a) is a genetically determined independent risk factor for the development of atherosclerosis. Today, it is unclear if direct interventions and treatments of Lp(a) help change patient outcomes from a cardiac standpoint. However, given that it is a known risk factor for heart disease, a team-based effort is required to minimize the patient's other cardiac risks to improve cardiac outcomes. Lipid therapy often requires an interprofessional healthcare team approach to achieve maximum success for the patient. The clinician oversees the prescription of lipid therapy medications, installs appropriate lifestyle modifications, and makes appropriate referrals. Treatment of more advanced lipid disorders benefits from having a pharmacist and dietitian involved to ensure appropriate medication protocols are in place and optimized dietary interventions are instituted. This team-based effort is vital in preventative cardiology for the patient population. Lp(a) testing is an essential tool in cardiovascular risk assessment, requiring the collective efforts of a multidisciplinary healthcare team. By fostering communication, standardizing protocols, and emphasizing patient education, healthcare teams can enhance their ability to provide comprehensive care, ultimately leading to improved patient outcomes in cardiovascular health.