Lipoprotein(a) Elevation: A New Diagnostic Code with Relevance to Service Members and Veterans

LDLC reduction alone leaves a residual CVD risk that is greater than the risk reduced.40 In addition, the autoimmune inflammation and lipid specific autoantibodies play an important role in increased CVD morbidity and mortality risk. ^70,71 The presence of autoantibodies such as antiphospholipid antibodies (without a specific autoimmune disease diagnosis) increases the risk of subclinical atherosclerosis. ^72,73 Certain autoimmune diseases such as systemic lupus erythematosus are recognized as independent risk factors for CVD. ^74,75 Autoantibodies appear to mediate CVD events and mortality risk, independent of traditional therapies for risk reduction. ⁷³ Further research is needed to clarify the role of autoantibodies as markers of increased or decreased CVD risk and their mechanism of action.

Autoantibodies directed at new antigens in lipoproteins within atherosclerotic lesions can modulate the impact of atherosclerosis via activation of the innate and adaptive immune system. ⁷⁶ The lipid-associated neopeptides are recognized as damage-associated or danger- associated molecular patterns (DAMPs), also known as alarmins, which signal molecules that can trigger and perpetuate noninfectious inflammatory responses. ^77-79 Plasma autoantibodies (immunoglobulin M and G [IgM, IgG]) modify proinflammatory oxidation-specific epitopes on oxidized phospholipids (oxPL) within lipoproteins and are linked with markers of inflammation and CVD events. ^80-82 Modified LDLC and ApoB-100 immune complexes with specific autoantibodies in the IgG class are associated with increased CVD. ⁷⁶ These and other risk-modulating autoantibodies may explain some of the variability in CVD outcomes by ethnicity and between individuals.

Some antibodies to oxidized LDL (ox-LDL) may have a protective role in the development of atherosclerosis. ^83,84 In a cohort of > 500 women, the number of carotid atherosclerotic plaques and total carotid plaque area were inversely correlated with a specific IgM autoantibody (MDA-p210). ⁸⁴ High concentrations of Lp(a)- containing circulating immune complexes and Lp(a)-specific IgM and IgG have been described in patients with coronary heart disease (CHD). ⁸⁵ Like ox-LDL, oxidized Lp(a) [ox-Lp(a)] is more potent than native Lp(a) in increasing atherosclerosis risk and is increased in patients with CHD compared to healthy controls. ^86-88 Ox-Lp(a) levels may represent an even stronger risk marker for CVD than ox-LDL. ⁸⁵

Possible Mechanisms of Pathogenesis

While the precise quantification of Lp(a) in human plasma (or serum) has been challenging, current clinical laboratories use standardized international reference reagents and controls in their assays. Most current Lp(a) assays are based on immunological methods (eg, immunonephelometry, immunoturbidimetry, or enzyme linked immunosorbent assay [ELISA]) using antibodies against apo(a). ⁸⁹ Apo(a) contains 10 subtypes of kringle IV and 1 copy of kringle V. Some assays use antibodies against kringle-IV type 2; however, it has been recommended that newer methods should use antibodies against the specific bridging kringle-IV Type 9 domain, which has a more stable bond and is present as a single copy. ^48,89 Other approaches to Lp(a) measurement include ultraperformance liquid chromatography/mass spectrometry that can determine both the concentration and particle size of apo(a). ^48,90 For routine clinical care, currently available assays reporting in mg/dL can be considered fairly accurate for separating low-risk from moderate-to-high-risk patients. ⁴⁵

The physiologic role of Lp(a) in humans remains to be fully defined and individuals with extremely low plasma Lp(a) levels present no disease or deficiency syndromes. ⁹¹ Lp(a) accumulates in endothelial injuries and binds to components of the vessel wall and subendothelial matrix, presumably due to the strong lysine binding site in apo(a). ⁴⁶ Mediated by apo(a), the binding stimulates chemotactic activation of monocytes/macrophages and thereby modulating angiogenesis and inflammation. ⁸⁹ Lp(a) may contribute to CVD and CAVS via its LDL-like component, with proinflammatory effects of oxidized phospholipids (OxPL) on both ApoB and apo(a) and antifibrinolytic/prothrombotic effects of apo(a). ⁹² In Vitro studies have demonstrated that apo(a) modifies cellular function of cultured vascular endothelial cells (promoting stress fiber formation, endothelial contraction and vascular permeability), smooth muscles, and monocytes/ macrophages (promoting differentiation of proinflammatory M1-1 type macrophages) via complex mechanisms of cell signaling and cytokine production.89 Lp(a) is the only monogenetic risk factor for aortic valve calcification and stenosis ⁹³ and is strongly linked specifically with the single nucleotide polymorphism (SNP) rs10455872 in the gene LPA encoding for apo(a). ⁹⁴