ABSTRACT Elevated levels of lipoprotein(a) (Lp(a)) are an independent risk factor for the development of atherothrombotic diseases. However, it is unknown if Lp(a) directly promotes thrombus formation, inhibits thrombus clearance, or merely accelerates the underlying atherosclerotic processes that culminate in plaque rupture. While numerous studies indicate that the apolipoprotein(a) (apo(a)) component of Lp(a) can inhibit plasminogen activation and fibrinolysis, recent evidence suggests that these effects may not be retained in Lp(a). An alternative mechanism through which Lp(a) may promote atherothrombotic events is by impacting platelet function. However, the effects of Lp(a) on platelet function and thrombosis have never been directly assessed in blood clots formed from flowing whole blood. Using a transgenic mouse model expressing high plasma concentrations of apo(a), we showed using a laser-induced mesenteric vessel injury model employing intravital microscopy that apo(a) increased platelet and fibrin volumes in the thrombi without affecting fibrinolysis. In a ferric chloride-induced mouse carotid artery thrombosis model, we found that apo(a) substantially reduced occlusion times and led to more stable thrombi; importantly, we also demonstrated that the effects of Lp(a) could be mitigated by low-dose aspirin therapy. We evaluated the prothrombotic potential of Lp(a) in human blood clots formed under arterial flow conditions using a Chandler loop apparatus. In these studies, we showed that the presence of Lp(a) during thrombogenesis inhibited lysis of the thrombi, without directly impacting fibrinolysis. Lp(a) promoted platelet accumulation in the Chandler thrombi and facilitated the development of fibrin networks that displayed features of fibrinolysis resistance. In an analysis of the UK Biobank, participants with Lp(a) ≥125 nmol/L had a higher risk for arterial thrombosis of non-atherosclerotic etiology but not a higher risk for venous thromboembolism. Collectively, these findings demonstrate that Lp(a) is inherently prothrombotic and likely promotes arterial thrombosis in vivo in part through promoting platelet activation. These findings explain how elevated Lp(a) is an important risk factor for arterial thrombosis either with or without an atherosclerotic etiology as well as observational primary prevention data suggesting that aspirin reduces atherothrombotic risk specifically in patients with elevated Lp(a).

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an important risk factor for several cardiovascular diseases. However, to date, elevated Lp(a) levels have not been directly targeted by clinicians because Lp(a) levels are almost entirely genetically determined and are comparatively resistant to standard lipid-lowering therapies. This unmet medical need might soon be addressed with the advent of potent Lp(a)-lowering therapies.

Lipoprotein(a) (Lp(a)) is a genetically determined causal risk factor for cardiovascular disease, with approximately 20% of the population exhibiting elevated levels. While there are promising drugs in development, there are currently no approved therapies specifically designed to lower Lp(a) levels. For high-risk individuals with extreme levels of Lp(a), liver-directed genome editing could be an effective one-time solution. Genome editing approaches such as CRISPR and TALENs can reduce Lp(a) in LPA-transgenic mouse models, but they frequently induce large and potentially harmful genomic deletions. Here, we report the first application of TadA-derived cytosine base editing (CBE), delivered via helper-dependent adenovirus (HDAdV) and adeno-associated virus (AAV) vectors, to introduce premature stop codons into LPA. This strategy produced robust and durable lowering of circulating apolipoprotein(a) (apo(a)) in LPA-transgenic mice. Using SMRT-seq with single-molecule unique molecular identifiers, we quantified deletion events and found that CBE did not induce large deletions when targeting a single LPA site and produced only a small fraction (<4%) of large deletions when editing across multiple sites. In contrast, CRISPR-Cas9 cutting of LPA resulted primarily in large deletions. These findings demonstrate that CBE enables sustained reduction of circulating apolipoprotein(a) in an LPA-transgenic mouse model while largely preserving genomic integrity.

PURPOSE OF REVIEW:Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are a causal and independent risk factor for atherosclerotic cardiovascular disease and an emerging therapeutic target. However, despite Lp(a) being on the cusp of widespread clinical consideration, fundamental questions regarding the pathophysiology of Lp(a) remain, most notably its contribution to atherothrombosis. This review will summarize recent evidence for both indirect and direct prothrombotic roles of Lp(a). RECENT FINDINGS:Preclinical studies show that the proinflammatory properties of Lp(a) - largely attributable to its cargo of oxidized phospholipids - promote vulnerable plaques through effects on vascular and immune/inflammatory cells. Advanced imaging techniques show that elevated Lp(a) is associated with vulnerable plaque phenotypes in patients. Regarding thrombosis, previous assumptions that Lp(a) is antifibrinolytic have given way to an emerging picture that Lp(a) promotes a lysis-resistant clot architecture while stimulating the coagulation cascade and potentiating platelet responses. Indeed, clinical studies have demonstrated that patients with elevated Lp(a) specifically accrue clinical benefit from aspirin in the primary prevention setting. SUMMARY:That elevated Lp(a) is both directly and indirectly prothrombotic remains to be proven by additional clinical and animal model studies Nonetheless, the accumulating evidence indicates that considering the prothrombotic activities of Lp(a) will impact clinical management of Lp(a) and the deployment of Lp(a)-lowering therapies.

Elevated plasma concentration of lipoprotein(a) is a highly prevalent, independent, and causal risk factor for the development of numerous cardiovascular diseases. This review summarizes the key clinical evidence for elevated lipoprotein(a) as a risk factor for atherosclerotic cardiovascular disease, aortic stenosis, and abdominal aortic aneurysm. These data are specifically linked to ongoing developments in understanding the pathophysiological mechanisms of lipoprotein(a) in these contexts. Highly potent lipoprotein(a)-lowering therapies are being studied in cardiovascular outcomes trials for their ability to prevent major adverse coronary events and aortic stenosis progression, potentially ushering in a new era of clinical management of lipoprotein(a).

Elevated levels of lipoprotein (a) [Lp(a)], an apolipoprotein B particle, are causally linked to atherosclerotic cardiovascular disease (ASCVD). Lp(a) is thought to promote ASCVD through multiple mechanisms, including its effects on cholesterol transport, inflammation, and thrombosis. This study defines the mechanisms that integrate Lp(a)-mediated cholesterol accumulation, inflammation, and thrombosis. In this study, we employed systems biology approaches, including proteomics, transcriptomics, and mass cytometry, to define the immune cellular and molecular phenotypes in patients with ASCVD having high and low Lp(a) levels and the molecular mechanisms through which Lp(a) mediates monocyte-driven inflammation and thrombosis. In 64 stable patients with ASCVD (41 with high Lp(a) [median Lp(a) 228.7 nmol/L] and 23 with low Lp(a) [median Lp(a) 17.8 nmol/L]), we found that circulating markers of inflammation (CCL28, IL-17D) and vascular dysfunction (tissue factor [TF]; 6.4 vs. 5.7 normalized protein expression (NPX); P = 0.01) were elevated in patients with high Lp(a) levels compared with those with low Lp(a) levels. Although total monocyte and hsCRP levels were similar between the groups, CD14+ monocytes from patients with ASCVD having an elevated Lp(a) were primed and expressed more TF at baseline and in response to stress. Mechanistically, we found that Lp(a) itself can activate monocytes through Toll-like receptor 2 (TLR2) and nuclear factor kappa B (NFκB) signaling, driving both the induction of TF and TF activity. Overall, these studies are the first to link Lp(a) to monocyte-mediated inflammation and thrombosis. This study demonstrates a novel mechanism through TLR2, NFκB, and monocyte TF by which Lp(a) amplifies immunothrombotic risk.

Introduction: Elevated plasma levels of Lp(a) are an independent, causal risk factor for cardiovascular diseases. Plasma Lp(a) concentration depends mainly on Lp(a) production rate in hepatocytes, which is mediated by intracellular non-covalent complexes between weak lysine binding sites in apo(a) kringles IV types 7 and 8 (LBS7,8) with apoB. Lp(a) is smaller, denser and more cholesterol-rich than VLDL, and Lp(a)-apoB is secreted at a lower rate than VLDL-apoB. Thus, Lp(a) and VLDL may follow different intracellular assembly and trafficking pathways. VLDL secretory trafficking has been reported to involve SURF4-containing, TANGO1-dependent, expanded COPII VLDL transport vesicles (VTV). However, the mechanisms causing differences in lipidation and apolipoprotein composition of Lp(a) compared to VLDL remain unclear. Hypothesis: The intracellular interaction between apo(a) and apoB diverts nascent Lp(a) from VTVs and hence impacts its secretion rate and lipidation. Methods: HuH7 cells were transfected with plasmids encoding either 17K (wild-type) or 17K△LBS7,8 apo(a) and incubated with oleic acid to stimulate lipoprotein assembly. Lp(a) secretion was assessed by immunoblot of medium from cells also transfected with siRNAs targeting expression of the VLDL-associated proteins SURF4, TM6SF2, FITM2, MTP or TANGO1. Interactions between apo(a), apoB and the VLDL ER cargo receptor, SURF4 were studied by pulldown assays. Confocal and super resolution radial fluctuation (SRRF) microscopy were used to assess apo(a)-apoB intracellular colocalization. Results: Knockdown of SURF4, TM6SF2, FITM2, and MTP using siRNA reduced apo(a) and apoB secretion. The reduction in apo(a) secretion was dependent upon the weak lysine binding sites present in apo(a) KIV types 7 and 8 in the case of siRNAs against TM6SF2 and MTP but not SURF4. Surprisingly, TANGO1 siRNA reduced apoB secretion, but increased apo(a) secretion. Pulldowns showed that apo(a) transfection reduced SURF4-apoB binding; this decrease was dependent on apo(a)-apoB interactions. Using SRRF microscopy, colocalization of apo(a), apoB and SURF4 was observed. Conclusions: Our findings suggest a role for several new players in the apo(a)-apoB secretion pathway and highlight the difference in secretory trafficking mechanisms between Lp(a) and VLDL. SURF4 may act as an ER-cargo receptor for apo(a) secretory trafficking, albeit potentially independent of the apo(a)-apoB interaction.

Introduction: Elevated levels of lipoprotein(a) (Lp(a)) are a risk factor for atherothrombotic events, however the direct contribution of Lp(a) to arterial thrombosis remains unclear. Lp(a) consists of a low-density lipoprotein (LDL)-like moiety linked to apolipoprotein(a) (apo(a)). Lp(a) contains proinflammatory oxidized phospholipids (OxPLs) on apo(a) and on the lipoprotein component of Lp(a), and has potential proinflammatory and prothrombotic properties which are not well understood. NETosis is a form of programmed cell death in which neutrophil extracellular traps (NETs), consisting of exteriorized chromatin, are released in response to inflammation, thereby contributing to immunothrombosis. We hypothesized that Lp(a) can stimulate NETosis; we assessed this by measuring the effect of purified Lp(a) on NETosis using an in vitro assay. Methods: Neutrophils were obtained by differentiation of the HL-60 cells (human promyelocytic leukemia cell line). Neutrophils were treated with phorbol 12-myristate 13-acetate (PMA), a NETosis trigger, in the absence or presence of 250 nmol/L purified Lp(a). NETosis was measured at time points up to 8 hours using a DNA-binding fluorescent dye to measure the extent of chromatin extrusion. Results: A dose-dependent increase in fluorescence was observed, with the greatest NETosis observed between 15.6 nM and 125 nM PMA treatment. We observed that Lp(a) treatment alone did not stimulate NETosis. However, in the differentiated HL-60 cell line, increased NETosis was observed in response to PMA stimulation in the presence of Lp(a), indicating that Lp(a) can potentiate NETosis. Compared to PMA treatment alone, NETosis was initiated earlier and occurs at a higher rate in the presence of Lp(a). Conclusion: We demonstrate, for the first time, that Lp(a) can potentiate NETosis. We predict that this effect may contribute to the prothrombotic effects of Lp(a) in the vasculature through stimulation of coagulation as well as inhibition of fibrinolysis. Future studies will also measure the response of PMA-treated neutrophils to purified apo(a) recombinant apo(a) species either containing or lacking proinflammatory OxPLs. Our findings improve our understanding of the pathogenic mechanisms of Lp(a) and contribute a new perspective to the field through exploration of the possible link between proinflammatory OxPLs on Lp(a) and its potential prothrombotic properties.

Elevated plasma concentrations of Lp(a) (lipoprotein(a)) are an independent and causal risk factor for the development of atherosclerotic cardiovascular diseases, including peripheral artery disease (PAD). Although proatherosclerotic, proinflammatory, procalcific, and prothrombotic effects have been attributed to Lp(a), the precise pathogenic mechanisms by which Lp(a) contributes to these disorders are unclear. Moreover, whether Lp(a) contributes in different ways to atherosclerotic cardiovascular diseases in different vascular sites has not been explored. In particular, PAD involves atherosclerotic plaque rupture and subsequent thrombosis in vessels above the knee, but medial arterial calcification leading to vessel stiffness and thrombosis below the knee; the significance of Lp(a) in these contexts is unclear. Elevated Lp(a) is associated with the spectrum of PAD outcomes, including incident claudication, PAD progression, lower limb revascularization, restenosis, major adverse leg events, including limb amputation, and death and hospitalization due to PAD. Overall, elevated Lp(a) is as potent a risk factor for PAD as it is for coronary artery disease. Reducing Lp(a) to mitigate risk of PAD and to treat patients with PAD, therefore, remains a substantial unmet clinical need, although studies are underway to assess the efficacy of RNA-directed Lp(a)-lowering therapies in preventing atherosclerotic cardiovascular disease events. Mounting clinical trials of these therapies to specifically address their effect on PAD events is the next key step.

Purpose of review Elevated plasma lipoprotein(a) (Lp(a)) is a causal and independent risk factor for atherosclerotic cardiovascular disease; therefore, understanding the fundamental mechanisms underlying Lp(a)-mediated pathogenesis is of significant clinical importance. This review summarizes recent advances in understanding the precise cellular targets of Lp(a) in atherogenesis, uncovering potential therapeutic avenues worth exploring. Recent findings Genetic evidence reveals that Lp(a) is six-fold more atherogenic per particle than LDL, and clinical imaging studies show increased atherosclerotic plaque burden and severity in patients with elevated Lp(a). A novel study using human monocytes uncovered diacylglycerols and lysophosphatidic acid as lipid species that contribute to the pro-inflammatory impacts of Lp(a), independent of the known pro-inflammatory oxidized phospholipids. The identification of a novel cell-surface receptor on endothelial cells involved in Lp(a) uptake offers another exploratory direction in vascular cells involved in atherosclerosis. Several studies have also pointed to accelerated coagulation as a potential target of Lp(a), involving Lp(a)-mediated impacts on platelet aggregation and monocyte tissue factor expression. Summary An understanding of these cell-specific targets of Lp(a) in atherogenesis will aid the Lp(a) field in identifying novel therapeutic targets for patients with elevated Lp(a), for whom few available therapeutic strategies currently exist.

Background: Elevated levels of lipoprotein(a) (Lp[a]) are a causal risk factor for atherosclerotic cardiovascular disease. Similarities between the apolipoprotein(a) (apo [a]) component of Lp(a) and plasminogen suggest that antifibrinolytic properties may account for the pathological effects of Lp(a). However, the antifibrinolytic effects of apo(a) do not appear to be retained by the complete Lp(a) particle. Objectives: We evaluated the effects of Lp(a), apo(a), and various apo(a) variants on clot formation and lysis times, thrombin generation, plasminogen activation, and fibrin architectures in ex vivo plasma clots. We also constructed predictive protein models to gain insight into the apo(a)-plasminogen interaction. Results: Apo(a) strongly inhibited fibrinolysis, an effect dependent on the presence of the apo(a) protease domain and mediated by Lys216 in this domain. Modeling of apo(a) suggests that Lys216 is blocked from binding to plasminogen in the Lp(a) particle by the presence of the apoB-containing lipoprotein. Lp(a) and apo(a) shortened plasma clot formation times, and accounting for this revealed a small but significant prolongation of fibrinolysis by Lp(a). The procoagulant effects involved the development of lysis-resistant clot architectures and were mediated through the strong lysine-binding site in apo(a) kringle IV type 10. In addition, Lp(a) (but not apo[a]) accelerated thrombin generation. Conclusions: The strong antifibrinolytic effects of apo(a) do not appear to be retained in the complete Lp(a) particle. However, Lp(a) and apo(a) displayed procoagulant effects, in part dependent on the kringle 4-like lysine-binding site. Further analysis is required to determine whether these reported procoagulant effects of Lp(a) impact thrombosis in vivo.

PURPOSE OF REVIEW:Elevated plasma lipoprotein(a) [Lp(a)] is a causal and independent risk factor for atherosclerotic cardiovascular disease and an emerging therapeutic target. Over the past 15 years, many medical bodies from around the world have released scientific statements and clinical guidelines regarding Lp(a). This review tracks how recommendations on Lp(a) have evolved over this timeframe. RECENT FINDINGS:Powerful studies demonstrating the independent association of elevated Lp(a) in large numbers of patients have been published. The data allowed a more precise formulation of risk categories for Lp(a) levels and of models for how a given level of Lp(a) in a moderate-risk to high-risk primary prevention patient might inform management of modifiable risk factors such as LDL cholesterol. Guidelines and statements have increasingly recommended universal screening for elevated Lp(a) and have identified elevated Lp(a) as a risk-enhancing or amplifying factor. However, some gaps and inconsistencies remain. SUMMARY:Ongoing cardiovascular outcomes trials of potent Lp(a)-lowering therapies will inform clinical use of Lp(a) in the future. Presently, consensus is building for measurement of Lp(a) in all adults and for incorporation of Lp(a) levels into clinical decision-making for prevention of cardiovascular disease. However, caution is warranted as the evidence base underlying this consensus has several important missing pieces.

ADAMTS13, a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13, regulates the length of Von Willebrand factor (VWF) multimers and their platelet-binding activity. ADAMTS13 is constitutively secreted as an active protease and is not inhibited by circulating protease inhibitors. Therefore, the mechanisms that regulate ADAMTS13 protease activity are unknown. We performed an unbiased proteomics screen to identify ligands of ADAMTS13 by optimizing the application of BioID to plasma. Plasma BioID identified 5 plasma proteins significantly labeled by the ADAMTS13-birA* fusion, including VWF and plasminogen. Glu-plasminogen, Lys-plasminogen, mini-plasminogen, and apo(a) bound ADAMTS13 with high affinity, whereas micro-plasminogen did not. None of the plasminogen variants or apo(a) bound to a C-terminal truncation variant of ADAMTS13 (MDTCS). The binding of plasminogen to ADAMTS13 was attenuated by tranexamic acid or ε-aminocaproic acid, and tranexamic acid protected ADAMTS13 from plasmin degradation. These data demonstrate that plasminogen is an important ligand of ADAMTS13 in plasma by binding to the C-terminus of ADAMTS13. Plasmin proteolytically degrades ADAMTS13 in a lysine-dependent manner, which may contribute to its regulation. Adapting BioID to identify protein-interaction networks in plasma provides a powerful new tool to study protease regulation in the cardiovascular system.

Lipoprotein(a) [Lp(a)] is a cardiovascular risk factor, and there is considerable interest in developing Lp(a)-lowering therapeutics for cardiovascular prevention. Current commercial Lp(a) assays measure total apolipoprotein(a) [apo(a)] and may be insufficient to accurately measure Lp(a) concentrations and determine Lp(a) lowering by a new class of small-molecule Lp(a) formation inhibitors such as muvalaplin. We developed a novel immunoassay that measures only Lp(a) particles. This intact Lp(a) assay demonstrated robust analytical performance, was insensitive to apo(a) isoform size, and correlated with a liquid chromatography-tandem mass spectrometry method. Muvalaplin phase I multiple ascending dose study samples and lepodisiran, a small-interfering RNA that lowers Lp(a), phase I single ascending dose study samples were analyzed using the intact Lp(a) assay and commercial assays. The Lp(a)-lowering efficacy of muvalaplin was underestimated by the commercial assay measuring total apo(a) compared with the intact Lp(a) assay specifically measuring Lp(a) particles. In contrast, the Lp(a)-lowering effect of lepodisiran was clinically comparable between the intact Lp(a) assay and commercial assay. This novel intact Lp(a) assay provides a more accurate approach for the assessment of Lp(a)-lowering agents and the study of Lp(a)-associated risk compared with currently available assays.

Background Thrombin-activatable fibrinolysis inhibitor (TAFI) is a plasma zymogen that provides a molecular link between coagulation and fibrinolysis. Studies have shown that the presence of glycosaminoglycans accelerates TAFI activation by plasmin and stabilizes TAFIa. Objectives We aimed to define the elements of TAFI structure that allow these effects. Methods Based on crystallographic studies and homology to heparin-binding proteins, we performed mutagenesis of surface-exposed charged residues on TAFI that putatively constitute heparin-binding sites. We determined heparin binding, kinetics of activation by plasmin in the presence or absence of heparin, thermal stability and antifibrinolytic potential of each variant. Results Mutagenesis of Lys211 and Lys212 did not impair heparin binding but affected the ability of TAFI to be activated by plasmin. Mutagenesis of Lys306 and His308 did not impair heparin binding but mutation of His308 had a severe negative effect on TAFI/TAFIa function. Mutation of Arg320 and Lys324 in combination markedly decreased heparin binding but had no effect on heparin-mediated acceleration of TAFI activation by plasmin while somewhat decreasing TAFIa stabilization by heparin. Mutagenesis of Lys327 and Arg330 decreased (but did not eliminate) heparin binding while decreasing the ability of heparin to accelerate plasmin-mediated TAFI activation, stabilize TAFIa, and increase the antifibrinolytic ability of TAFIa. A quadruple mutant of Arg320, Lys324, Lys327, and Arg330 completely lost heparin-binding ability and stabilization of the enzyme by heparin. Conclusions Basic residues in the dynamic flap of TAFIa define a functionally-relevant heparin binding site, but additional heparin-binding sites may be present on TAFI.

Elevated plasma levels of lipoprotein(a) (Lp(a)) are a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease. Lp(a) consists of a lipoprotein particle resembling low density lipoprotein and the covalently-attached glycoprotein apolipoprotein(a) (apo(a)). Novel therapeutics that specifically and potently lower Lp(a) levels are currently in advanced stages of clinical development, including in large, phase 3 cardiovascular outcomes trials. However, fundamental unanswered questions remain concerning some key aspects of Lp(a) biosynthesis and catabolism as well as the true pathogenic mechanisms of the particle. In this review, we describe the salient biochemical features of Lp(a) and apo(a) and how they underlie the disease-causing potential of Lp(a), the factors that determine plasma Lp(a) concentrations, and the mechanism of action of Lp(a)-lowering drugs.

Elevated plasma concentrations of lipoprotein(a) [Lp(a)] are recognized as an independent and causal risk factor for a variety of cardiovascular diseases, including coronary heart disease and calcific aortic valve stenosis. Lp(a) is a unique class of apolipoprotein B-100 (apoB)–containing lipoprotein, consisting of the unique glycoprotein apolipoprotein(a) [apo(a)] which is covalently linked to apoB. Apo(a) contains 10 types of plasminogen kringle IV–like domains as well as a kringle V–like domain and an inactive protease-like domain. The KIV type 2 (KIV2) domain is present in identically repeated copies from 3 to >40 copies, which gives rise to differently sized Lp(a) isoforms in the population. Lp(a) levels are under strong genetic control, with the LPA gene [which encodes apo(a)] itself being the major determinant; the size polymorphism of LPA, in turn, plays the largest role in influencing Lp(a), as apo(a) size is inversely related to apo(a) production rate and hence Lp(a) levels. Importantly, Lp(a) levels are relatively resistant to lifestyle and existing therapeutic interventions that are effective in lowering low-density lipoprotein cholesterol (LDL-C); the molecular details of Lp(a) biosynthesis and catabolism remain largely obscure. In addition, the mechanisms by which Lp(a) promotes cardiovascular disease have yet to be definitively identified; proatherosclerotic, proinflammatory, and prothrombotic mechanisms have been described. Many challenges must be overcome before Lp(a) can be widely adopted as a screening and treatment target in the clinic, including lack of standardization and harmonization of Lp(a) measurement arising from the unique structure of Lp(a). Controversy exists as to whether Lp(a) should be routinely measured as part of clinical risk assessment. However, with the ongoing development of therapies that specifically lower Lp(a), in particular an antisense oligonucleotide currently in phase 3 cardiovascular outcomes trials, a new era for Lp(a) could soon dawn.

BACKGROUND:Lipoprotein(a) [Lp(a)] is a driver of residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) decrease Lp(a) with significant heterogeneity in response. We investigated contributors to the heterogeneous response. METHODS:Cholesterol Reduction and Residual Risk in Diabetes (CHORD) was a prospective study examining lipid lowering in participants with a low-density lipoprotein cholesterol (LDL-C) > 100 mg/dL with and without diabetes (DM) on lipid lowering therapy (LLT) for 30-days with evolocumab 140 mg every 14 days combined with either atorvastatin 80 mg or ezetimibe 10 mg daily. Lp(a) level was measured by immunoturbidometry, and the apolipoprotein(a) [apo(a)] isoform size was measured by denaturing agarose gel electrophoresis and Western blotting. We examined the change in Lp(a) levels from baseline to 30 days. RESULTS:Among 150 participants (mean age 50 years, 58% female, 50% non-White, 17% Hispanic, 50% DM), median (interquartile range) Lp(a) was 27.5 (8-75) mg/dL at baseline and 23 (3-68) mg/dL at 30 days, leading to a 10% (0-36) median reduction (P < .001). Among 73 (49%) participants with Lp(a) ≥ 30 mg/dL at baseline, there was a 15% (3-25) median reduction in Lp(a) (P < .001). While baseline Lp(a) level was not correlated with change in Lp(a) (r = 0.04, P = .59), apo(a) size directly correlated with Lp(a) reduction (P < .001). After adjustment for age, sex, race/ethnicity, DM, and type of LLT, apo(a) size remained positively associated with a reduction in Lp(a) (Beta 0.95, 95% confidence interval, 0.93-0.97, P < .001). CONCLUSION:Our data demonstrate variation in Lp(a) reduction with potent LLT. Change in Lp(a) was strongly associated with apo(a) isoform size.

BACKGROUND: Case-control, intervention and laboratory studies have demonstrated a link between apolipoprotein B (ApoB)-containing lipoproteins and clot structure and thrombosis. There is, however, limited evidence on a population level. OBJECTIVES: We determined the cross-sectional relationship between lipoprotein(a) [Lp(a)], lowdensity lipoprotein cholesterol (LDL-C), and ApoB with fibrinogen and plasma clot properties in 1462 Black South Africans, a population with higher fibrinogen and Lp(a) levels compared with individuals of European descent. METHODS: Data were obtained from participants in the South African arm of the Prospective Urban and Rural Epidemiology study. Clot properties analyzed included lag time, slope, maximum absorbance, and clot lysis time (turbidity). Lp(a) was measured in nM using particle-enhanced immunoturbidimetry. General linear models (GLM) were used to determine the associations between ApoB and ApoB-containing lipoproteins with fibrinogen and plasma clot properties. Stepwise regression was used to determine contributors to clot properties and Lp(a) variance. RESULTS: GLM and regression results combined, indicated fibrinogen concentration and rate of clot formation (slope) had the strongest association with Lp(a); clot density associated positively with both Lp(a) and LDL-C; time to clot formation associated negatively with ApoB; and clot lysis time (CLT) demonstrated strong positive associations with both ApoB and LDL-C, while its association with Lp(a) was fibrinogen concentration dependent.