Publications by authors named "Calvin Yeang"

41 Publications

Clonal hematopoiesis driven by DNMT3A and TET2 mutations: role in monocyte and macrophage biology and atherosclerotic cardiovascular disease.

Curr Opin Hematol 2022 Jan;29(1):1-7

Sulpizio Cardiovascular Center, Division of Cardiology, University of California San Diego, La Jolla, California, USA.

Purpose Of Review: Clonal hematopoiesis of indeterminate potential (CHIP), defined by the presence of somatic mutations in hematopoietic cells, is associated with advanced age and increased mortality due to cardiovascular disease. Gene mutations in DNMT3A and TET2 are the most frequently identified variants among patients with CHIP and provide selective advantage that spurs clonal expansion and myeloid skewing. Although DNMT3A and TET2 appear to have opposing enzymatic influence on DNA methylation, mounting data has characterized convergent inflammatory pathways, providing insights to how CHIP may mediate atherosclerotic cardiovascular disease (ASCVD).

Recent Findings: We review a multitude of studies that characterize aberrant inflammatory signaling as result of DNMT3A and TET2 deficiency in monocytes and macrophages, immune cells with prominent roles in atherosclerosis. Although specific DNA methylation signatures associated with these known epigenetic regulators have been identified, many studies have also characterized diverse modulatory functions of DNTM3A and TET2 that urge cell and context-specific experimental studies to further define how DNMT3A and TET2 may nonenzymatically activate inflammatory pathways with clinically meaningful consequences.

Summary: CHIP, common in elderly individuals, provides an opportunity understand and potentially modify age-related chronic inflammatory ASCVD risk.
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http://dx.doi.org/10.1097/MOH.0000000000000688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639635PMC
January 2022

Lipoprotein(a): A Genetically Determined, Causal, and Prevalent Risk Factor for Atherosclerotic Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Arterioscler Thromb Vasc Biol 2021 Oct 14:ATV0000000000000147. Epub 2021 Oct 14.

High levels of lipoprotein(a) [Lp(a)], an apoB100-containing lipoprotein, are an independent and causal risk factor for atherosclerotic cardiovascular diseases through mechanisms associated with increased atherogenesis, inflammation, and thrombosis. Lp(a) is predominantly a monogenic cardiovascular risk determinant, with ≈70% to ≥90% of interindividual heterogeneity in levels being genetically determined. The 2 major protein components of Lp(a) particles are apoB100 and apolipoprotein(a). Lp(a) remains a risk factor for cardiovascular disease development even in the setting of effective reduction of plasma low-density lipoprotein cholesterol and apoB100. Despite its demonstrated contribution to atherosclerotic cardiovascular disease burden, we presently lack standardization and harmonization of assays, universal guidelines for diagnosing and providing risk assessment, and targeted treatments to lower Lp(a). There is a clinical need to understand the genetic and biological basis for variation in Lp(a) levels and its relationship to disease in different ancestry groups. This scientific statement capitalizes on the expertise of a diverse basic science and clinical workgroup to highlight the history, biology, pathophysiology, and emerging clinical evidence in the Lp(a) field. Herein, we address key knowledge gaps and future directions required to mitigate the atherosclerotic cardiovascular disease risk attributable to elevated Lp(a) levels.
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http://dx.doi.org/10.1161/ATV.0000000000000147DOI Listing
October 2021

Novel method for quantification of lipoprotein(a)-cholesterol: implications for improving accuracy of LDL-C measurements.

J Lipid Res 2021 Feb 24;62:100053. Epub 2021 Feb 24.

Vascular Medicine Program, Sulpizio Cardiovascular Center, Division of Cardiology, University of California San Diego, La Jolla, CA, USA. Electronic address:

Current methods for determining "LDL-C" in clinical practice measure the cholesterol content of both LDL and lipoprotein(a) [Lp(a)-C]. We developed a high-throughput, sensitive, and rapid method to quantitate Lp(a)-C and improve the accuracy of LDL-C by subtracting for Lp(a)-C (LDL-C). Lp(a)-C is determined following isolation of the Lp(a) on magnetic beads linked to monoclonal antibody LPA4 recognizing apolipoprotein(a). This Lp(a)-C assay does not detect cholesterol in plasma samples lacking Lp(a) and is linear up to 747 nM Lp(a). To validate this method clinically over a wide range of Lp(a) (9.0-822.8 nM), Lp(a)-C and LDL-C were determined in 21 participants receiving an Lp(a)-specific lowering antisense oligonucleotide and in eight participants receiving placebo at baseline, at 13 weeks during peak drug effect, and off drug. In the groups combined, Lp(a)-C ranged from 0.6 to 35.0 mg/dl and correlated with Lp(a) molar concentration (r = 0.76; P < 0.001). However, the percent Lp(a)-C relative to Lp(a) mass varied from 5.8% to 57.3%. Baseline LDL-C was lower than LDL-C [mean (SD), 102.2 (31.8) vs. 119.2 (32.4) mg/dl; P < 0.001] and did not correlate with Lp(a)-C. It was demonstrated that three commercially available "direct LDL-C" assays also include measures of Lp(a)-C. In conclusion, we have developed a novel and sensitive method to quantitate Lp(a)-C that provides insights into the Lp(a) mass/cholesterol relationship and may be used to more accurately report LDL-C and reassess its role in clinical medicine.
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http://dx.doi.org/10.1016/j.jlr.2021.100053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042377PMC
February 2021

Low-Density Lipoprotein Cholesterol Corrected for Lipoprotein(a) Cholesterol, Risk Thresholds, and Cardiovascular Events.

J Am Heart Assoc 2020 12 23;9(23):e016318. Epub 2020 Nov 23.

Division of Cardiovascular Medicine Sulpizio Cardiovascular Center University of California, San Diego La Jolla CA.

Background Conventional "low-density lipoprotein cholesterol (LDL-C)" assays measure cholesterol content in both low-density lipoprotein and lipoprotein(a) particles. To clarify the consequences of this methodological limitation for clinical care, our study aimed to compare associations of "LDL-C" and corrected LDL-C with risk of cardiovascular disease and to assess the impact of this correction on the classification of patients into guideline-recommended LDL-C categories. Methods and Results Lipoprotein(a) cholesterol content was estimated as 30% of lipoprotein(a) mass and subtracted from "LDL-C" to obtain corrected LDL-C values (LDL-C). Hazard ratios for cardiovascular disease (defined as coronary heart disease, stroke, or coronary revascularization) were quantified by individual-patient-data meta-analysis of 5 statin landmark trials from the Lipoprotein(a) Studies Collaboration (18 043 patients; 5390 events; 4.7 years median follow-up). When comparing top versus bottom quartiles, the multivariable-adjusted hazard ratio for cardiovascular disease was significant for "LDL-C" (1.17; 95% CI, 1.05-1.31; =0.005) but not for LDL-C (1.07; 95% CI, 0.93-1.22; =0.362). In a routine laboratory database involving 531 144 patients, reclassification of patients across guideline-recommended LDL-C categories when using LDL-C was assessed. In "LDL-C" categories of 70 to <100, 100 to <130, 130 to <190, and ≥190 mg/dL, significant proportions (95% CI) of participants were reassigned to lower LDL-C categories when LDL-C was used: 30.2% (30.0%-30.4%), 35.1% (34.9%-35.4%), 32.9% (32.6%-33.1%), and 41.1% (40.0%-42.2%), respectively. Conclusions LDL-C" was associated with incident cardiovascular disease only when lipoprotein(a) cholesterol content was included in its measurement. Refinement in techniques to accurately measure LDL-C, particularly in patients with elevated lipoprotein(a) levels, is warranted to assign risk to the responsible lipoproteins.
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http://dx.doi.org/10.1161/JAHA.119.016318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763787PMC
December 2020

The interconnection between lipoprotein(a), lipoprotein(a) cholesterol and true LDL-cholesterol in the diagnosis of familial hypercholesterolemia.

Curr Opin Lipidol 2020 12;31(6):305-312

Vascular Medicine Program, Sulpizio Cardiovascular Center, Division of Cardiology, University of California San Diego, La Jolla, California, USA.

Purpose Of Review: Elevated levels of lipoprotein(a) [Lp(a)] are present in 30-50% of patients with familial hypercholesterolemia. The contribution of Lp(a) towards risk stratification of patients with familial hypercholesterolemia has been recently recognized, with studies showing a significantly worse prognosis if Lp(a) is elevated. However, the role of elevated Lp(a) in diagnosis of familial hypercholesterolemia is less well defined or accepted.

Recent Findings: An important confounder in the diagnosis of familial hypercholesterolemia is the significant contribution of the cholesterol content on Lp(a) (Lp(a)-C) in individuals with elevated Lp(a). Because Lp(a)-C is incorporated into all clinical LDL-C measurements, it can contribute significantly to the cholesterol threshold diagnostic criteria for familial hypercholesterolemia used in most clinical algorithms.

Summary: In this review, we discuss the interrelationship of Lp(a), Lp(a)-C and correct LDL-C in the diagnosis and prognosis of familial hypercholesterolemia. Future studies of accurately measuring correct LDL-C or in using apoB-100 and Lp(a) criteria may overcome the limitations of using estimated LDL-C in the diagnosis of familial hypercholesterolemia in individuals with concomitant elevation of Lp(a).
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http://dx.doi.org/10.1097/MOL.0000000000000713DOI Listing
December 2020

Generation and characterization of LPA-KIV9, a murine monoclonal antibody binding a single site on apolipoprotein (a).

J Lipid Res 2020 09 8;61(9):1263-1270. Epub 2020 Jul 8.

Vascular Medicine Program, Sulpizio Cardiovascular Center, Division of Cardiology, University of California San Diego, La Jolla, CA, USA

Lipoprotein (a) [Lp(a)] is a risk factor for CVD and a target of therapy, but Lp(a) measurements are not globally standardized. Commercially available assays generally use polyclonal antibodies that detect multiple sites within the kringle (K)IV repeat region of Lp(a) and may lead to inaccurate assessments of plasma levels. With increasing awareness of Lp(a) as a cardiovascular risk factor and the active clinical development of new potential therapeutic approaches, the broad availability of reagents capable of providing isoform independence of Lp(a) measurements is paramount. To address this issue, we generated a murine monoclonal antibody that binds to only one site on apo(a). A BALB/C mouse was immunized with a truncated version of apo(a) that contained eight total KIV repeats, including only one copy of KIV We generated hybridomas, screened them, and successfully produced a KIV-independent monoclonal antibody, named LPA-KIV9. Using a variety of truncated apo(a) constructs to map its binding site, we found that LPA-KIV9 binds to KIV without binding to plasminogen. Fine peptide mapping revealed that LPA-KIV9 bound to the sequence LETPTVV on KIV In conclusion, the generation of monoclonal antibody LPA-KIV9 may be a useful reagent in basic research studies and in the clinical application of Lp(a) measurements.
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http://dx.doi.org/10.1194/jlr.RA120000830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469883PMC
September 2020

Short-term regulation of hematopoiesis by lipoprotein(a) results in the production of pro-inflammatory monocytes.

Int J Cardiol 2020 09 7;315:81-85. Epub 2020 May 7.

Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Department of Internal Medicine, Amsterdam University Medical Centers, VU University, Amsterdam, the Netherlands; Department of Hematology, Amsterdam University Medical Centers, VU University, Amsterdam, the Netherlands. Electronic address:

Background: Lipoproteins are important regulators of hematopoietic stem and progenitor cell (HSPC) biology, predominantly affecting myelopoiesis. Since myeloid cells, including monocytes and macrophages, promote the inflammatory response that propagates atherosclerosis, it is of interest whether the atherogenic low-density lipoprotein (LDL)-like particle lipoprotein(a) [Lp(a)] contributes to atherogenesis via stimulating myelopoiesis.

Methods & Results: To assess the effects of Lp(a)-priming on long-term HSPC behavior we transplanted BM of Lp(a) transgenic mice, that had been exposed to elevated levels of Lp(a), into lethally-irradiated C57Bl6 mice and hematopoietic reconstitution was analyzed. No differences in HSPC populations or circulating myeloid cells were detected ten weeks after transplantation. Likewise, in vitro stimulation of C57Bl6 BM cells for 24 h with Lp(a) did not affect colony formation, total cell numbers or myeloid populations 7 days later. To assess the effects of elevated levels of Lp(a) on myelopoiesis, C57Bl6 bone marrow (BM) cells were stimulated with lp(a) for 24 h, and a marked increase in granulocyte-monocyte progenitors, pro-inflammatory Ly6 monocytes and macrophages was observed. Seven days of continuous exposure to Lp(a) increased colony formation and enhanced the formation of pro-inflammatory monocytes and macrophages. Antibody-mediated neutralization of oxidized phospholipids abolished the Lp(a)-induced effects on myelopoiesis.

Conclusion: Lp(a) enhances the production of inflammatory monocytes at the bone marrow level but does not induce cell-intrinsic long-term priming of HSPCs. Given the short-term and direct nature of this effect, we postulate that Lp(a)-lowering treatment has the capacity to rapidly revert this multi-level inflammatory response.
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http://dx.doi.org/10.1016/j.ijcard.2020.05.008DOI Listing
September 2020

Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation.

Circ Res 2020 05 12;126(10):1346-1359. Epub 2020 Mar 12.

From the Experimental Vascular Medicine (J.G.S., L.A., J.C.B., M.V., A.K.G., J.K.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands.

Rationale: Patients with elevated levels of lipoprotein(a) [Lp(a)] are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of a proinflammatory state.

Objective: We hypothesized that Lp(a) induces endothelial cell inflammation by rewiring endothelial metabolism.

Methods And Results: We evaluated the impact of Lp(a) on the endothelium and describe that Lp(a), through its oxidized phospholipid content, activates arterial endothelial cells, facilitating increased transendothelial migration of monocytes. Transcriptome analysis of Lp(a)-stimulated human arterial endothelial cells revealed upregulation of inflammatory pathways comprising monocyte adhesion and migration, coinciding with increased 6-phophofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)-3-mediated glycolysis. ICAM (intercellular adhesion molecule)-1 and PFKFB3 were also found to be upregulated in carotid plaques of patients with elevated levels of Lp(a). Inhibition of PFKFB3 abolished the inflammatory signature with concomitant attenuation of transendothelial migration.

Conclusions: Collectively, our findings show that Lp(a) activates the endothelium by enhancing PFKFB3-mediated glycolysis, leading to a proadhesive state, which can be reversed by inhibition of glycolysis. These findings pave the way for therapeutic agents targeting metabolism aimed at reducing inflammation in patients with cardiovascular disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.316206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208285PMC
May 2020

ApoCIII-Lp(a) complexes in conjunction with Lp(a)-OxPL predict rapid progression of aortic stenosis.

Heart 2020 05 13;106(10):738-745. Epub 2020 Feb 13.

Department of cardiology, University of California San Diego, La Jolla, California, USA

Objective: This study assessed whether apolipoprotein CIII-lipoprotein(a) complexes (ApoCIII-Lp(a)) associate with progression of calcific aortic valve stenosis (AS).

Methods: Immunostaining for ApoC-III was performed in explanted aortic valve leaflets in 68 patients with leaflet pathological grades of 1-4. Assays measuring circulating levels of ApoCIII-Lp(a) complexes were measured in 218 patients with mild-moderate AS from the AS Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial. The progression rate of AS, measured as annualised changes in peak aortic jet velocity (V), and combined rates of aortic valve replacement (AVR) and cardiac death were determined. For further confirmation of the assay data, a proteomic analysis of purified Lp(a) was performed to confirm the presence of apoC-III on Lp(a).

Results: Immunohistochemically detected ApoC-III was prominent in all grades of leaflet lesion severity. Significant interactions were present between ApoCIII-Lp(a) and Lp(a), oxidised phospholipids on apolipoprotein B-100 (OxPL-apoB) or on apolipoprotein (a) (OxPL-apo(a)) with annualised V (all p<0.05). After multivariable adjustment, patients in the top tertile of both apoCIII-Lp(a) and Lp(a) had significantly higher annualised V (p<0.001) and risk of AVR/cardiac death (p=0.03). Similar results were noted with OxPL-apoB and OxPL-apo(a). There was no association between autotaxin (ATX) on ApoB and ATX on Lp(a) with faster progression of AS. Proteomic analysis of purified Lp(a) showed that apoC-III was prominently present on Lp(a).

Conclusion: ApoC-III is present on Lp(a) and in aortic valve leaflets. Elevated levels of ApoCIII-Lp(a) complexes in conjunction with Lp(a), OxPL-apoB or OxPL-apo(a) identify patients with pre-existing mild-moderate AS who display rapid progression of AS and higher rates of AVR/cardiac death.

Trial Registration: NCT00800800.
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http://dx.doi.org/10.1136/heartjnl-2019-315840DOI Listing
May 2020

Ancient Remedy for a Modern Disease: Will Celastrol Become a Treatment for Aortic Valve Stenosis?

JACC Basic Transl Sci 2020 Jan 27;5(1):50-52. Epub 2020 Jan 27.

Vascular Medicine Program, Sulpizio Cardiovascular Center, Division of Cardiovascular Diseases, University of California-San Diego, La Jolla, California.

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http://dx.doi.org/10.1016/j.jacbts.2019.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000881PMC
January 2020

Statins and increases in Lp(a): an inconvenient truth that needs attention.

Eur Heart J 2020 01;41(1):192-193

Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, USA.

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http://dx.doi.org/10.1093/eurheartj/ehz776DOI Listing
January 2020

Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis.

J Lipid Res 2019 12 24;60(12):2082-2089. Epub 2019 Sep 24.

Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA

It is postulated that lipoprotein (a) [Lp(a)] inhibits fibrinolysis, but this hypothesis has not been tested in humans due to the lack of specific Lp(a) lowering agents. Patients with elevated Lp(a) were randomized to antisense oligonucleotide [IONIS-APO(a)] directed to apo(a) ( = 7) or placebo ( = 10). Ex vivo plasma lysis times and antigen concentrations of plasminogen, factor XI, plasminogen activator inhibitor 1, thrombin activatable fibrinolysis inhibitor, and fibrinogen at baseline, day 85/92/99 (peak drug effect), and day 190 (3 months off drug) were measured. The mean ± SD baseline Lp(a) levels were 477.3 ± 55.9 nmol/l in IONIS-APO(a) and 362.1 ± 89.9 nmol/l in placebo. The mean± SD percentage change in Lp(a) for IONIS-APO(a) was -69.3 ± 12.2% versus -5.4 ± 6.9% placebo ( < 0.0010) at day 85/92/99 and -15.6 ± 8.9% versus 3.2 ± 12.2% ( = 0.003) at day 190. Clot lysis times and coagulation/fibrinolysis-related biomarkers showed no significant differences between IONIS-APO(a) and placebo at all time points. Clot lysis times were not affected by exogenously added Lp(a) at concentrations up to 200 nmol/l to plasma with very low (12.5 nmol/l) Lp(a) levels, whereas recombinant apo(a) had a potent antifibrinolytic effect. In conclusion, potent reductions of Lp(a) in patients with highly elevated Lp(a) levels do not affect ex vivo measures of fibrinolysis; the relevance of any putative antifibrinolytic effects of Lp(a) in vivo needs further study.
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http://dx.doi.org/10.1194/jlr.P094763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889713PMC
December 2019

Statin therapy increases lipoprotein(a) levels.

Eur Heart J 2020 06;41(24):2275-2284

Department of Medicine, Division of Endocrinology and Metabolism, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0682, USA.

Aims: Lipoprotein(a) [Lp(a)] is elevated in 20-30% of people. This study aimed to assess the effect of statins on Lp(a) levels.

Methods And Results: This subject-level meta-analysis includes 5256 patients (1371 on placebo and 3885 on statin) from six randomized trials, three statin-vs.-placebo trials, and three statin-vs.-statin trials, with pre- and on-treatment (4-104 weeks) Lp(a) levels. Statins included atorvastatin 10 mg/day and 80 mg/day, pravastatin 40 mg/day, rosuvastatin 40 mg/day, and pitavastatin 2 mg/day. Lipoprotein(a) levels were measured with the same validated assay. The primary analysis of Lp(a) is based on the log-transformed data. In the statin-vs.-placebo pooled analysis, the ratio of geometric means [95% confidence interval (CI)] for statin to placebo is 1.11 (1.07-1.14) (P < 0.0001), with ratio >1 indicating a higher increase in Lp(a) from baseline in statin vs. placebo. The mean percent change from baseline ranged from 8.5% to 19.6% in the statin groups and -0.4% to -2.3% in the placebo groups. In the statin-vs.-statin pooled analysis, the ratio of geometric means (95% CI) for atorvastatin to pravastatin is 1.09 (1.05-1.14) (P < 0.0001). The mean percent change from baseline ranged from 11.6% to 20.4% in the pravastatin group and 18.7% to 24.2% in the atorvastatin group. Incubation of HepG2 hepatocytes with atorvastatin showed an increase in expression of LPA mRNA and apolipoprotein(a) protein.

Conclusion: This meta-analysis reveals that statins significantly increase plasma Lp(a) levels. Elevations of Lp(a) post-statin therapy should be studied for effects on residual cardiovascular risk.
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http://dx.doi.org/10.1093/eurheartj/ehz310DOI Listing
June 2020

Lipoprotein(a) in Patients Undergoing Transcatheter Aortic Valve Replacement.

Angiology 2019 Apr 30;70(4):332-336. Epub 2019 Jan 30.

1 Division of Cardiovascular Diseases, Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California San Diego, San Diego, CA, USA.

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for calcific aortic valve stenosis (CAVS) for which transcatheter aortic valve replacement (TAVR) is increasingly utilized as treatment. We evaluated the effect of a program to increase testing of and define the prevalence of elevated Lp(a) among patients undergoing TAVR. Educational efforts and incorporation of a "check-box" Lp(a) order to the preoperative TAVR order set were instituted. Retrospective chart review was performed in 229 patients requiring TAVR between May 2013 and September 2018. Of these patients, 57% had an Lp(a) level measured; testing rates increased from 0% in 2013 to 96% in 2018. Lipoprotein(a) testing occurred in 11% of patients before and in 80% of patients after the "check-box" order set ( P < .001). The prevalence of elevated Lp(a) (≥30 mg/dL) was 35%; these patients had a higher incidence of coronary artery disease requiring revascularization compared with patients with normal Lp(a) (65% vs 47%; P = .047). Patients with Lp(a) ≥30 mg/dL also had higher incidence of paravalvular leak compared with those with normal Lp(a) (13% vs 4%; P = .04). This study defines the prevalence of elevated Lp(a) in advanced stages of CAVS and provides a practice pathway to assess procedural complications and long-term outcomes of TAVR in patients with elevated Lp(a) levels.
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http://dx.doi.org/10.1177/0003319719826461DOI Listing
April 2019

Association of Mild to Moderate Aortic Valve Stenosis Progression With Higher Lipoprotein(a) and Oxidized Phospholipid Levels: Secondary Analysis of a Randomized Clinical Trial.

JAMA Cardiol 2018 12;3(12):1212-1217

Vascular Medicine Program, University of California, San Diego, La Jolla.

Importance: Several studies have reported an association of levels of lipoprotein(a) (Lp[a]) and the content of oxidized phospholipids on apolipoprotein B (OxPL-apoB) and apolipoprotein(a) (OxPL-apo[a]) with faster calcific aortic valve stenosis (CAVS) progression. However, whether this association is threshold or linear remains unclear.

Objective: To determine whether the plasma levels of Lp(a), OxPL-apoB, and OxPL-apo(a) have a linear association with a faster rate of CAVS progression.

Design, Setting, And Participants: This secondary analysis of a randomized clinical trial tested the association of baseline plasma levels of Lp(a), OxPL-apoB, and OxPL-apo(a) with the rate of CAVS progression. Participants were included from the ASTRONOMER (Effects of Rosuvastatin on Aortic Stenosis Progression) trial, a multicenter study conducted in 23 Canadian sites designed to test the effect of statin therapy (median follow-up, 3.5 years [interquartile range, 2.9-4.5 years]). Patients with mild to moderate CAVS defined by peak aortic jet velocity ranging from 2.5 to 4.0 m/s were recruited; those with peak aortic jet velocity of less than 2.5 m/s or with an indication for statin therapy were excluded. Data were collected from January 1, 2002, through December 31, 2005, and underwent ad hoc analysis from April 1 through September 1, 2018.

Interventions: After the randomization process, patients were followed up by means of echocardiography for 3 to 5 years.

Main Outcomes And Measures: Progression rate of CAVS as assessed by annualized progression of peak aortic jet velocity.

Results: In this cohort of 220 patients (60.0% male; mean [SD] age, 58 [13] years), a linear association was found between plasma levels of Lp(a) (odds ratio [OR] per 10-mg/dL increase, 1.10; 95% CI, 1.03-1.19; P = .006), OxPL-apoB (OR per 1-nM increase, 1.06; 95% CI, 1.01-1.12; P = .02), and OxPL-apo(a) (OR per 10-nM increase, 1.16; 95% CI, 1.05-1.27; P = .002) and faster CAVS progression, which is marked in younger patients (OR for Lp[a] level per 10-mg/dL increase, 1.19 [95% CI, 1.07-1.33; P = .002]; OR for OxPL-apoB level per 1-nM increase, 1.06 [95% CI, 1.02-1.17; P = .01]; and OR for OxPL-apo[a] level per 10-nM increase, 1.26 [95% CI, 1.10-1.45; P = .001]) and remained statistically significant after comprehensive multivariable adjustment (β coefficient, ≥ 0.25; SE, ≤ 0.004 [P ≤ .005]; OR, ≥1.10 [P ≤ .007]).

Conclusions And Relevance: This study demonstrates that the association of Lp(a) levels and its content in OxPL with faster CAVS progression is linear, reinforcing the concept that Lp(a) levels should be measured in patients with mild to moderate CAVS to enhance management and risk stratification.

Trial Registration: ClinicalTrials.gov Identifier: NCT00800800.
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http://dx.doi.org/10.1001/jamacardio.2018.3798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583098PMC
December 2018

Publisher Correction: Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice.

Nature 2018 09;561(7724):E43

Department of Medicine, University of California, San Diego, La Jolla, CA, USA.

In this Letter, affiliation number 1 was originally missing from the HTML; the affiliations were missing for author Ming-Yow Hung in the HTML; and the Fig. 4 legend erroneously referred to panels a-h, instead of a-g. These errors have been corrected online.
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http://dx.doi.org/10.1038/s41586-018-0313-xDOI Listing
September 2018

Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice.

Nature 2018 06 6;558(7709):301-306. Epub 2018 Jun 6.

Department of Medicine, University of California, San Diego, La Jolla, CA, USA.

Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes . Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL. Here, to determine the role of OxPL in vivo in the context of atherogenesis, we generated transgenic mice in the Ldlr background that expressed a single-chain variable fragment of E06 (E06-scFv) using the Apoe promoter. E06-scFv was secreted into the plasma from the liver and macrophages, and achieved sufficient plasma levels to inhibit in vivo macrophage uptake of OxLDL and to prevent OxPL-induced inflammatory signalling. Compared to Ldlr mice, Ldlr E06-scFv mice had 57-28% less atherosclerosis after 4, 7 and even 12 months of 1% high-cholesterol diet. Echocardiographic and histologic evaluation of the aortic valves demonstrated that E06-scFv ameliorated the development of aortic valve gradients and decreased aortic valve calcification. Both cholesterol accumulation and in vivo uptake of OxLDL were decreased in peritoneal macrophages, and both peritoneal and aortic macrophages had a decreased inflammatory phenotype. Serum amyloid A was decreased by 32%, indicating decreased systemic inflammation, and hepatic steatosis and inflammation were also decreased. Finally, the E06-scFv prolonged life as measured over 15 months. Because the E06-scFv lacks the functional effects of an intact antibody other than the ability to bind OxPL and inhibit OxLDL uptake in macrophages, these data support a major proatherogenic role of OxLDL and demonstrate that OxPL are proinflammatory and proatherogenic, which E06 counteracts in vivo. These studies suggest that therapies inactivating OxPL may be beneficial for reducing generalized inflammation, including the progression of atherosclerosis, aortic stenosis and hepatic steatosis.
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http://dx.doi.org/10.1038/s41586-018-0198-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033669PMC
June 2018

Reduction of myocardial ischaemia-reperfusion injury by inactivating oxidized phospholipids.

Cardiovasc Res 2019 01;115(1):179-189

Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.

Aims: Myocardial ischaemia followed by reperfusion (IR) causes an oxidative burst resulting in cellular dysfunction. Little is known about the impact of oxidative stress on cardiomyocyte lipids and their role in cardiac cell death. Our goal was to identify oxidized phosphatidylcholine-containing phospholipids (OxPL) generated during IR, and to determine their impact on cell viability and myocardial infarct size.

Methods And Results: OxPL were quantitated in isolated rat cardiomyocytes using mass spectrophotometry following 24 h of IR. Cardiomyocyte cell death was quantitated following exogenously added OxPL and in the absence or presence of E06, a 'natural' murine monoclonal antibody that binds to the PC headgroup of OxPL. The impact of OxPL on mitochondria in cardiomyocytes was also determined using cell fractionation and Bnip expression. Transgenic Ldlr-/- mice, overexpressing a single-chain variable fragment of E06 (Ldlr-/--E06-scFv-Tg) were used to assess the effect of inactivating endogenously generated OxPL in vivo on myocardial infarct size. Following IR in vitro, isolated rat cardiomyocytes showed a significant increase in the specific OxPLs PONPC, POVPC, PAzPC, and PGPC (P < 0.05 to P < 0.001 for all). Exogenously added OxPLs resulted in significant death of rat cardiomyocytes, an effect inhibited by E06 (percent cell death with added POVPC was 22.6 ± 4.14% and with PONPC was 25.3 ± 3.4% compared to 8.0 ± 1.6% and 6.4 ± 1.0%, respectively, with the addition of E06, P < 0.05 for both). IR increased mitochondrial content of OxPL in rat cardiomyocytes and also increased expression of Bcl-2 death protein 3 (Bnip3), which was inhibited in presence of E06. Notably cardiomyocytes with Bnip3 knock-down were protected against cytotoxic effects of OxPL. In mice exposed to myocardial IR in vivo, compared to Ldlr-/- mice, Ldlr-/--E06-scFv-Tg mice had significantly smaller myocardial infarct size normalized to area at risk (72.4 ± 21.9% vs. 47.7 ± 17.6%, P = 0.023).

Conclusions: OxPL are generated within cardiomyocytes during IR and have detrimental effects on cardiomyocyte viability. Inactivation of OxPL in vivo results in a reduction of infarct size.
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http://dx.doi.org/10.1093/cvr/cvy136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302283PMC
January 2019

Relationship between "LDL-C", estimated true LDL-C, apolipoprotein B-100, and PCSK9 levels following lipoprotein(a) lowering with an antisense oligonucleotide.

J Clin Lipidol 2018 May - Jun;12(3):702-710. Epub 2018 Mar 1.

Ionis Pharmaceuticals, Carlsbad, CA, USA; Division of Cardiovascular Medicine, University of California San Diego, La Jolla, CA, USA. Electronic address:

Background: The laboratory measurement of "low-density lipoprotein cholesterol (LDL-C)" includes the cholesterol content of lipoprotein(a) (Lp(a)-C).

Objective: To estimate the "true" LDL-C in relation to changes in apolipoprotein B-100 (apoB-100) and assess changes in proprotein convertase subtilisin/kexin 9 (PCSK9) levels in patients with elevated Lp(a) treated with IONIS-APO(a) METHODS: A pooled placebo group (n = 29), and cohort A (n = 24, baseline Lp(a) 50-175 mg/dL) and cohort B (n = 8, baseline Lp(a) > 175 mg/dL) treated with IONIS-APO(a) were studied. Lp(a) particle number, ultracentrifugation-measured "LDL-C", apoB-100, total PCSK9, and lipoprotein-associated PCSK9 (PCSK9-Lp(a), PCSK9-apoB, PCSK9-apoAI) were measured. Lp(a)-cholesterol (Lp(a)-C) and LDL-C corrected for Lp(a)-C (LDL-C) were calculated.

Results: Baseline mean (standard deviation) "LDL-C" was 120 (42), 128 (45), and 112 (39) mg/dL in placebo, cohorts A and B, respectively, whereas LDL-C was 86 (48), 96 (43), and 57 (37) mg/dL (P < .001 compared with placebo), representing 28%, 25%, and 50% lower levels than "LDL-C". Following IONIS-APO(a) treatment at day 85/99, Lp(a) particle number and Lp(a)-C decreased -66.8% and -71.6%, apoB-100 -10.3% and -17.5%, "LDL-C" -11.8% and -22.7%, (P < .001 for all vs placebo), whereas LDL-C increased +10.4% (P = .66) and +49.9% (P < .001) in cohorts A and B, respectively. Total PCSK9 did not change but PCSK9-Lp(a) decreased with IONIS-APO(a) vs placebo (-39.0% vs +8.4%, P < .001).

Conclusion: LDL-C is lower than laboratory "LDL-C" in patients with elevated Lp(a). Following apolipoprotein(a) inhibition and decline in Lp(a) and Lp(a)-C, the decline in apoB-100 is consistent with the notion that LDL devoid of apo(a) is cleared faster than Lp(a). These types of analyses may provide insights into the mechanisms of drugs affecting Lp(a) levels in clinical trials.
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http://dx.doi.org/10.1016/j.jacl.2018.02.014DOI Listing
September 2019

PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis.

J Am Coll Cardiol 2018 01;71(3):321-335

Division of Cardiovascular Diseases, Sulpizio Cardiovascular Center, Department of Medicine, University of California San Diego, La Jolla, California. Electronic address:

Background: Oxidation-specific epitopes (OSEs) are proinflammatory, and elevated levels in plasma predict cardiovascular events.

Objectives: The purpose of this study was to develop novel positron emission tomography (PET) probes to noninvasively image OSE-rich lesions.

Methods: An antigen-binding fragment (Fab) antibody library was constructed from human fetal cord blood. After multiple rounds of screening against malondialdehyde-acetaldehyde (MAA) epitopes, the Fab LA25 containing minimal nontemplated insertions in the CDR3 region was identified and characterized. In mice, pharmacokinetics, biodistribution, and plaque specificity studies were performed with Zirconium-89 (Zr)-labeled LA25. In rabbits, Zr-LA25 was used in combination with an integrated clinical PET/magnetic resonance (MR) system. F-fluorodeoxyglucose PET and dynamic contrast-enhanced MR imaging were used to evaluate vessel wall inflammation and plaque neovascularization, respectively. Extensive ex vivo validation was carried out through a combination of gamma counting, near infrared fluorescence, autoradiography, immunohistochemistry, and immunofluorescence.

Results: LA25 bound specifically to MAA epitopes in advanced and ruptured human atherosclerotic plaques with accompanying thrombi and in debris from distal protection devices. PET/MR imaging 24 h after injection of Zr-LA25 showed increased uptake in the abdominal aorta of atherosclerotic rabbits compared with nonatherosclerotic control rabbits, confirmed by ex vivo gamma counting and autoradiography. F-fluorodeoxyglucose PET, dynamic contrast-enhanced MR imaging, and near-infrared fluorescence signals were also significantly higher in atherosclerotic rabbit aortas compared with control aortas. Enhanced liver uptake was also noted in atherosclerotic animals, confirmed by the presence of MAA epitopes by immunostaining.

Conclusions: Zr-LA25 is a novel PET radiotracer that may allow noninvasive phenotyping of high-risk OSE-rich lesions.
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http://dx.doi.org/10.1016/j.jacc.2017.11.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995462PMC
January 2018

Lipoprotein(a) Associated Molecules are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis.

JACC Basic Transl Sci 2017 Jun 26;2(3):229-240. Epub 2017 Jun 26.

Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California San Diego, La Jolla CA.

The gene is the only monogenetic risk factor for calcific aortic valve stenosis (CAVS). Oxidized phospholipids (OxPL) and lysophosphatidic acid generated by autotaxin (ATX) from OxPL are pro-inflammatory. Aortic valve leaflets were categorized pathologically from Both ATX-apoB and ATX-apo(a) were measureable in plasma. Lp(a), autotaxin, OxPL and MDA epitopes progressively increased in immunostaining (p<0.001 for all). Six species of OxPL and LysoPA were identified following extraction from valve leaflets. The presence of a constellation of pathologically-linked, Lp(a)-associated molecules in plasma and in aortic valve leaflets of patients with CAVS suggest that Lp(a) is a key etiological factor in CAVS.
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http://dx.doi.org/10.1016/j.jacbts.2017.02.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685511PMC
June 2017

Novel Lipoprotein(a) Catabolism Pathway via Apolipoprotein(a) Recycling: Adding the Plasminogen Receptor PlgR to the List.

Circ Res 2017 03;120(7):1050-1052

From the Department of Medicine, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism (P.L.S.M.G.), University of California San Diego, La Jolla.

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http://dx.doi.org/10.1161/CIRCRESAHA.117.310700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470738PMC
March 2017

The Prevalence of Lipoprotein(a) Measurement and Degree of Elevation Among 2710 Patients With Calcific Aortic Valve Stenosis in an Academic Echocardiography Laboratory Setting.

Angiology 2017 Oct 10;68(9):795-798. Epub 2017 Jan 10.

1 Vascular Medicine Program, Sulpizio Cardiovascular Center, University of California, San Diego, San Diego, CA, USA.

Lipoprotein(a; Lp[a]) and its associated oxidized phospholipids are causal, genetic risk factors for calcific aortic valve stenosis (CAVS). We determined the prevalence of Lp(a) measurement among 2710 patients with CAVS and 1369 control patients (∼50% of study group) without CAVS with an echocardiogram between January 2010 and February 2016 in an academic echocardiography laboratory. Lipoprotein(a) measurements were performed at a referral laboratory using an isoform-independent assay. The prevalence of any Lp(a) measurement was 4.6% (124 of the 2710) in patients with CAVS and 3.1% (42 of the 1369) in the control group ( P = .021). In patients with CAVS, mean (standard deviation) Lp(a) levels were 38 (54) mg/dL and median (interquartile range) Lp(a) levels were 14 (6-48) mg/dL. Of the 124 patients with CAVS having Lp(a) measurements, 83 (66.9%) had Lp(a) <30 mg/dL and 41 (33.1%) had Lp(a) ≥30 mg/dL. This study reflects low physician testing of Lp(a) levels in CAVS. Given the role of Lp(a) as a causal risk factor for CAVS, and the ongoing development of therapies to normalize Lp(a) levels, our results suggest that Lp(a) measurements in CAVS should be more widely obtained in clinical practice.
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http://dx.doi.org/10.1177/0003319716688415DOI Listing
October 2017

Lipoprotein(a)-cholesterol levels estimated by vertical auto profile correlate poorly with Lp(a) mass in hyperlipidemic subjects: Implications for clinical practice interpretation of Lp(a)-mediated risk.

J Clin Lipidol 2016 Nov - Dec;10(6):1389-1396. Epub 2016 Sep 28.

Division of Cardiovascular Diseases, Department of Medicine, Sulpizio Cardiovascular Center, University of California, La Jolla, CA, USA. Electronic address:

Background: Lipoprotein(a) [Lp(a)] is generally measured as total mass of the entire particle or as apolipoprotein(a) particle number.

Objective: The cholesterol content of Lp(a) [Lp(a)-C)] can be estimated by the vertical auto profile (VAP) method. We assessed whether this is an accurate surrogate measurement of Lp(a) mass.

Methods: VAP-Lp(a)-C and VAP-high density lipoprotein cholesterol (HDL-C) estimated by the VAP technique, Lp(a) mass, oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) that primarily reflect OxPL on Lp(a), and HDL-C measured by enzymatic methods were measured in 552 hypercholesterolemic patients at baseline and 24 weeks after therapy with niacin monotherapy (N = 118), ezetimibe/simvastatin monotherapy (n = 155), or ezetimibe/simvastatin (10/20 mg) + niacin (to 2 g) (N = 279) in a randomized, double-blind trial.

Results: VAP-Lp(a)-C correlated only modestly with Lp(a) mass at baseline (r = 0.56, P < .001) and 24 weeks (r = 0.56, P < .001), explaining only 31% of the association. VAP-Lp(a)-C correlated with HDL-C at baseline (r = 0.34, P < .001) and 24 weeks (r = 0.30, P < .001) and with VAP-HDL-C at baseline (r = 39, P < .001) and 24 weeks (r = 0.33, P < .001). In contrast, Lp(a) mass did not correlate with HDL-C at baseline (r = 0.06, P = .12) and 24 weeks (r = -0.01 P = .91). Lp(a) mass correlated strongly with oxidized phospholipids on apolipoprotein B-100 at baseline (r = 0.81, P < .001) and 24 weeks (r = 0.79, P < .001). VAP-Lp(a)-C levels increased linearly with HDL-C and VAP-HDL-C quartiles (P < .001 for both) but Lp(a) mass did not. Quantitating the percent of cholesterol present on Lp(a) by dividing VAP-Lp(a)-C by Lp(a) mass revealed that 25% of patients had a percentage >100, which is not possible.

Conclusions: VAP-Lp(a)-C is a poor estimate for Lp(a) mass and likely reflects the content of HDL-C in the overlapping density spectrum of Lp(a) and HDL. These data suggest that patients with prior VAP-Lp(a)-C measurements may have misclassification of Lp(a)-related risk.
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http://dx.doi.org/10.1016/j.jacl.2016.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8545497PMC
October 2017

Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans.

Circulation 2016 Aug 5;134(8):611-24. Epub 2016 Aug 5.

From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.).

Background: Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent cardiovascular risk factor, but the underlying mechanisms responsible for its pathogenicity are poorly defined. Because Lp(a) is the prominent carrier of proinflammatory oxidized phospholipids (OxPLs), part of its atherothrombosis might be mediated through this pathway.

Methods: In vivo imaging techniques including magnetic resonance imaging, (18)F-fluorodeoxyglucose uptake positron emission tomography/computed tomography and single-photon emission computed tomography/computed tomography were used to measure subsequently atherosclerotic burden, arterial wall inflammation, and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed with fluorescence-activated cell sorter analysis, inflammatory stimulation assays, and transendothelial migration assays. In vitro studies of the pathophysiology of Lp(a) on monocytes were performed with an in vitro model for trained immunity.

Results: We show that subjects with elevated Lp(a) (108 mg/dL [50-195 mg/dL]; n=30) have increased arterial inflammation and enhanced peripheral blood mononuclear cells trafficking to the arterial wall compared with subjects with normal Lp(a) (7 mg/dL [2-28 mg/dL]; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce proinflammatory cytokines on stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the proinflammatory response in monocytes derived from healthy control subjects (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apolipoprotein(a).

Conclusions: These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates proinflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease.

Clinical Trial Registration: URL: http://www.trialregister.nl. Unique identifier: NTR5006 (VIPER Study).
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.020838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995139PMC
August 2016

Effect of therapeutic interventions on oxidized phospholipids on apolipoprotein B100 and lipoprotein(a).

J Clin Lipidol 2016 May-Jun;10(3):594-603. Epub 2016 Mar 8.

Division of Cardiovascular Diseases, Sulpizio Cardiovascular Center, Department of Medicine, University of California, La Jolla, CA, USA. Electronic address:

Background: Oxidized phospholipids (OxPL) on apolipoprotein B-100 (OxPL-apoB) reflect the biological activity of lipoprotein(a) (Lp[a]) and predict cardiovascular disease events. However, studies with statins and low-fat diets show increases in OxPL-apoB and Lp(a).

Objective: This study evaluated changes in OxPL-apoB and Lp(a) with extended-release niacin (N), ezetimibe/simvastatin (E/S) and combination E/S/N. A systematic literature review of previously published trials, measuring both OxPL-apoB and Lp(a) after therapeutic interventions, was also performed.

Methods: OxPL-apoB and Lp(a) were measured in 591 patients at baseline and 24 weeks after therapy with N, E/S, or E/S/N in a previously completed randomized trial of hypercholesterolemic patients. The literature review included 12 trials and 3896 patients evaluating statins, low-fat diets, antisense to apolipoprotein(a) and lipid apheresis.

Results: Niacin decreased OxPL-apoB levels (median [interquartile range]; 3.5 [2.2-9.2] nM to 3.1 [1.8-7.2] nM, P < .01) and Lp(a) (10.9 [4.6-38.4] to 9.3 [3.1-32.9] mg/dL, P < .01). In contrast, E/S and E/S/N significantly increased OxPL-apoB (3.5 [2.1-7.8] to 4.9 [3.0-11.1] nM, P < .01) and (3.3 [1.9-9.3] to 4.3 [2.6-11.2] nM, P < .01), respectively and Lp(a) (11.5 [6.1-36.4] to 14.9 [6.6-54.6] mg/dL, P < .01) and (11.3 [5.4-43.8] to 11.6 [5.9-52.8] mg/dL, P < .01), respectively. The systematic review of statins and diet demonstrated 23.8% and 21.3% mean increases in OxPL-apoB and 10.6% and 19.4% increases in Lp(a), respectively. However 44.1% and 52.0% decreases in OxPL-apoB and Lp(a), respectively, were present with Lp(a)-lowering therapies.

Conclusions: This study demonstrates differential changes in OxPL-apoB and Lp(a) with various lipid-lowering approaches. These changes in OxPL-apoB and Lp(a) may provide insights into the results and interpretation of recent cardiovascular disease outcomes trials.
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http://dx.doi.org/10.1016/j.jacl.2016.01.005DOI Listing
October 2017

Lipoprotein(a) and oxidized phospholipids in calcific aortic valve stenosis.

Curr Opin Cardiol 2016 07;31(4):440-50

Division of Cardiovascular Diseases, Sulpizio Cardiovascular Center, Department of Medicine, University of California San Diego, La Jolla, California, USA.

Purpose Of Review: As the incidence of calcific aortic valve stenosis increases with the aging of the population, improved understanding and novel therapies to reduce its progression and need for aortic valve replacement are urgently needed.

Recent Findings: Lipoprotein(a) is the only monogenetic risk factor for calcific aortic stenosis. Elevated levels are a strong, causal, independent risk factor, as demonstrated in epidemiological, genome-wide association studies and Mendelian randomization studies. Lipoprotein(a) is the major lipoprotein carrier of oxidized phospholipids, which are proinflammatory and promote calcification of vascular cells, two key pathophysiological drivers of aortic stenosis. Elevated plasma lipoprotein(a) and oxidized phospholipids predict progression of pre-existing aortic stenosis and need for aortic valve replacement. The failure of statin trials in pre-existing aortic stenosis may be partially due to an increase in lipoprotein(a) and oxidized phospholipid levels caused by statins. Antisense oligonucleotides targeted to apo(a) are in Phase 2 clinical development and shown to lower both lipoprotein(a) and oxidized phospholipids.

Summary: Lipoprotein(a) and oxidized phospholipids are key therapeutic targets in calcific aortic stenosis. Strategies aimed at potent lipoprotein(a) lowering to normalize levels and/or to suppress the proinflammatory effects of oxidized phospholipids may prevent progression of this disease.
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http://dx.doi.org/10.1097/HCO.0000000000000300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956483PMC
July 2016

PCSK9 Association With Lipoprotein(a).

Circ Res 2016 06 27;119(1):29-35. Epub 2016 Apr 27.

From the Department of Medicine, Center for Preventive Cardiology, Knight Cardiovascular Institute, Portland, OR (H.T., D.C., D.P., M.D.S., I.G., P.B.D., S.F.); School of Public Health, Oregon Health and Science University, Portland (J.M.); Sulpizio Cardiovascular Center, Vascular Medicine Program, University of California at San Diego, La Jolla (C.Y., S.T.); Inra UMR1280, Université de Nantes, CHU Hôtel-Dieu, Nantes, France (M.C., G.L.); Inserm UMR 1188, Sainte-Clotilde, France (G.L.); Université de la Réunion, Faculté de Médecine, Saint-Denis, France (G.L.); and CHU de la Réunion, Saint-Denis, France (G.L.).

Rationale: Lipoprotein(a) [Lp(a)] is a highly atherogenic low-density lipoprotein-like particle characterized by the presence of apoprotein(a) [apo(a)] bound to apolipoprotein B. Proprotein convertase subtilisin/kexin type 9 (PCSK9) selectively binds low-density lipoprotein; we hypothesized that it can also be associated with Lp(a) in plasma.

Objective: Characterize the association of PCSK9 and Lp(a) in 39 subjects with high Lp(a) levels (range 39-320 mg/dL) and in transgenic mice expressing either human apo(a) only or human Lp(a) (via coexpression of human apo(a) and human apolipoprotein B).

Methods And Results: We show that PCSK9 is physically associated with Lp(a) in vivo using 3 different approaches: (1) analysis of Lp(a) fractions isolated by ultracentrifugation; (2) immunoprecipitation of plasma using antibodies to PCSK9 and immunodetection of apo(a); (3) ELISA quantification of Lp(a)-associated PCSK9. Plasma PCSK9 levels correlated with Lp(a) levels, but not with the number of kringle IV-2 repeats. PCSK9 did not bind to apo(a) only, and the association of PCSK9 with Lp(a) was not affected by the loss of the apo(a) region responsible for binding oxidized phospholipids. Preferential association of PCSK9 with Lp(a) versus low-density lipoprotein (1.7-fold increase) was seen in subjects with high Lp(a) and normal low-density lipoprotein. Finally, Lp(a)-associated PCSK9 levels directly correlated with plasma Lp(a) levels but not with total plasma PCSK9 levels.

Conclusions: Our results show, for the first time, that plasma PCSK9 is found in association with Lp(a) particles in humans with high Lp(a) levels and in mice carrying human Lp(a). Lp(a)-bound PCSK9 may be pursued as a biomarker for cardiovascular risk.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.308811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920709PMC
June 2016

The role of lipoprotein(a) in progression of renal disease: Causality or reverse causality?

J Diabetes Complications 2016 07 7;30(5):755-7. Epub 2016 Apr 7.

Division of Cardiovascular Diseases, Sulpizio Cardiovascular Center, Department of Medicine, University of California, La Jolla, CA. Electronic address:

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http://dx.doi.org/10.1016/j.jdiacomp.2016.04.001DOI Listing
July 2016
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