Publications by authors named "Sotirios Tsimikas"

296 Publications

Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk.

Eur Heart J 2022 Jan 13. Epub 2022 Jan 13.

Department of Medicine, Université de Montréal and Ecogene-21 Clinical Research Centre, Chicoutimi, QC, Canada.

Aims: Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established cardiovascular disease.

Methods And Results: A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200-500 mg/dL (2.26-5.65 mmol/L). Patients received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. The primary endpoint was the percent change in fasting triglyceride levels from baseline to Month 6 of exposure. Baseline median (interquartile range) fasting triglyceride levels were 262 (222-329) mg/dL [2.96 (2.51-3.71) mmol/L]. Treatment with olezarsen resulted in mean percent triglyceride reductions of 23% with 10 mg every 4 weeks, 56% with 15 mg every 2 weeks, 60% with 10 mg every week, and 60% with 50 mg every 4 weeks, compared with increase by 6% for the pooled placebo group (P-values ranged from 0.0042 to <0.0001 compared with placebo). Significant decreases in apoC-III, very low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were also observed. There were no platelet count, liver, or renal function changes in any of the olezarsen groups. The most common adverse event was mild erythema at the injection site.

Conclusion: Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease.

Trial Registration Number: NCT03385239.

Key Question: This clinical trial evaluated olezarsen (APOCIII-LRx), an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III production, in lowering triglyceride levels.

Key Finding: Olezarsen (APOCIII-LRx) significantly reduced apolipoprotein C-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease.

Take Home Message: Targeting apoC-III with antisense oligonucleotides is a unique and potent approach that results in the substantial reduction of triglycerides and atherogenic lipoproteins. Olezarsen (APOCIII-LRx) may have a variety of applications in patients with hypertriglyceridaemia.
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http://dx.doi.org/10.1093/eurheartj/ehab820DOI Listing
January 2022

Lipoprotein(a), venous thromboembolism and COVID-19: A pilot study.

Atherosclerosis 2022 01 21;341:43-49. Epub 2021 Dec 21.

Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address:

Background And Aims: Thrombosis is a major driver of adverse outcome and mortality in patients with Coronavirus disease 2019 (COVID-19). Hypercoagulability may be related to the cytokine storm associated with COVID-19, which is mainly driven by interleukin (IL)-6. Plasma lipoprotein(a) [Lp(a)] levels increase following IL-6 upregulation and Lp(a) has anti-fibrinolytic properties. This study investigated whether Lp(a) elevation may contribute to the pro-thrombotic state hallmarking COVID-19 patients.

Methods: Lp(a), IL-6 and C-reactive protein (CRP) levels were measured in 219 hospitalized patients with COVID-19 and analyzed with linear mixed effects model. The baseline biomarkers and increases during admission were related to venous thromboembolism (VTE) incidence and clinical outcomes in a Kaplan-Meier and logistic regression analysis.

Results: Lp(a) levels increased significantly by a mean of 16.9 mg/dl in patients with COVID-19 during the first 21 days after admission. Serial Lp(a) measurements were available in 146 patients. In the top tertile of Lp(a) increase, 56.2% of COVID-19 patients experienced a VTE event compared to 18.4% in the lowest tertile (RR 3.06, 95% CI 1.61-5.81; p < 0.001). This association remained significant after adjusting for age, sex, IL-6 and CRP increase and number of measurements. Increases in IL-6 and CRP were not associated with VTE. Increase in Lp(a) was strongly correlated with increase in IL-6 (r = 0.44, 95% CI 0.30-0.56, p < 0.001).

Conclusions: Increases in Lp(a) levels during the acute phase of COVID-19 were strongly associated with VTE incidence. The acute increase in anti-fibrinolytic Lp(a) may tilt the balance to VTE in patients hospitalized for COVID-19.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8690577PMC
January 2022

Oxidized Phospholipids Promote NETosis and Arterial Thrombosis in LNK(SH2B3) Deficiency.

Circulation 2021 12 30;144(24):1940-1954. Epub 2021 Nov 30.

Molecular Medicine, Columbia University Medical Center, New York (H.D., W.L., T.F., K.E.-U., T.X., S.A., M.Y., B.H., N.W., A.R.T.).

Background: LNK/SH2B3 inhibits Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling by hematopoietic cytokine receptors. Genome-wide association studies have shown association of a common single nucleotide polymorphism in (R262W, T allele) with neutrophilia, thrombocytosis, and coronary artery disease. We have shown that ) reduces LNK function and that LNK-deficient mice display prominent platelet-neutrophil aggregates, accelerated atherosclerosis, and thrombosis. Platelet-neutrophil interactions can promote neutrophil extracellular trap (NET) formation. The goals of this study were to assess the role of NETs in atherosclerosis and thrombosis in mice with hematopoietic deficiency.

Methods: We bred mice with combined deficiency of and the NETosis-essential enzyme PAD4 (peptidyl arginine deiminase 4) and transplanted their bone marrow into mice. We evaluated the role of LNK in atherothrombosis in humans and mice bearing a gain of function variant in JAK2 (JAK2).

Results: -deficient mice displayed accelerated carotid artery thrombosis with prominent NETosis that was completely reversed by PAD4 deficiency. Thrombin-activated platelets promoted increased NETosis when incubated with neutrophils compared with wild-type platelets or wild-type neutrophils. This involved increased surface exposure and release of oxidized phospholipids (OxPL) from platelets, as well as increased priming and response of neutrophils to OxPL. To counteract the effects of OxPL, we introduced a transgene expressing the single-chain variable fragment of E06 (E06-scFv). E06-scFv reversed accelerated NETosis, atherosclerosis, and thrombosis in mice. We also showed increased NETosis when human induced pluripotent stem cell-derived ) neutrophils were incubated with ) platelet/megakaryocytes, but not in isogenic ) controls, confirming human relevance. Using data from the UK Biobank, we found that individuals with the JAK2 mutation only showed increased risk of coronary artery disease when also carrying the LNK R262W allele. Mice with hematopoietic and clonal hematopoiesis showed accelerated arterial thrombosis but not atherosclerosis compared with controls.

Conclusions: Hematopoietic deficiency promotes NETosis and arterial thrombosis in an OxPL-dependent fashion. LNK(R262W) reduces LNK function in human platelets and neutrophils, promoting NETosis, and increases coronary artery disease risk in humans carrying mutations. Therapies targeting OxPL may be beneficial for coronary artery disease in genetically defined human populations.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663540PMC
December 2021

Longitudinal Assessment of Lipoprotein(a) Levels in Perinatally HIV-Infected Children and Adolescents.

Viruses 2021 10 14;13(10). Epub 2021 Oct 14.

Department of Pediatric Infectious Diseases, Emma Children's Hospital, Amsterdam UMC, Location Academic Medical Center, 1100 DD Amsterdam, The Netherlands.

HIV is an independent risk factor of cardiovascular disease (CVD); therefore, perinatally HIV-infected (PHIV) children potentially have a greater CVD risk at older age. Lipoprotein(a) (Lp(a)) is an established risk factor for CVD in the general population. To evaluate a potential increased CVD risk for PHIV children, we determined their lipid profiles including Lp(a). In the first substudy, we assessed the lipid profiles of 36 PHIV children visiting the outpatient clinic in Amsterdam between 2012 and 2020. In the second substudy, we enrolled 21 PHIV adolescents and 23 controls matched for age, sex and ethnic background on two occasions with a mean follow-up time of 4.6 years. We assessed trends of lipid profiles and their determinants, including patient and disease characteristics, using mixed models. In the first substudy, the majority of PHIV children were Black (92%) with a median age of 8.0y (5.7-10.8) at first assessment. Persistent elevated Lp(a) levels were present in 21/36 (58%) children (median: 374 mg/L (209-747); cut off = 300). In the second substudy, the median age of PHIV adolescents was 17.5y (15.5-20.7) and of matched controls 16.4y (15.8-19.5) at the second assessment. We found comparable lipid profiles between groups. In both studies, increases in LDL-cholesterol and total cholesterol were associated with higher Lp(a) levels. A majority of PHIV children and adolescents exhibited elevated Lp(a) levels, probably associated with ethnic background. Nonetheless, these elevated Lp(a) levels may additionally contribute to an increased CVD risk.
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http://dx.doi.org/10.3390/v13102067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8539147PMC
October 2021

PCSK9 Activity Is Potentiated Through HDL Binding.

Circ Res 2021 11 4;129(11):1039-1053. Epub 2021 Oct 4.

King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, United Kingdom (S.A.B., E.D., R.L., K. Theofilatos, K. Takov, M.M.).

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.121.319272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579991PMC
November 2021

Always Present, But Now Rediscovered: Lp(a) as a Predictor of Long-Term Outcomes in PCI.

JACC Cardiovasc Interv 2021 09;14(18):2069-2072

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

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http://dx.doi.org/10.1016/j.jcin.2021.08.032DOI Listing
September 2021

Atherothrombotic factors and atherosclerotic cardiovascular events: the multi-ethnic study of atherosclerosis.

Eur Heart J 2021 Sep 11. Epub 2021 Sep 11.

Division of Cardiology, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA.

Aims: Traditional atherosclerotic cardiovascular disease (ASCVD) risk factors fail to address the full spectrum of the complex interplay of atherosclerotic and atherothrombotic factors integral to ASCVD events. This study sought to examine the association between atherothrombotic biomarkers and ASCVD events.

Methods And Results: The association between atherothrombotic biomarkers and 877 ASCVD events with and without adjustment for traditional risk factors was evaluated via Cox proportional hazards models and factor analysis in 5789 Multi-Ethnic Study of Atherosclerosis participants over a median follow-up of 14.7 years. Factor analysis accounted for multidimensional relationship and shared variance among study biomarkers, which identified two new variables: a thrombotic factor (Factor 1), principally defined by shared variance in fibrinogen, plasmin-antiplasmin complex, factor VIII, D-dimer, and lipoprotein(a), and a fibrinolytic factor (Factor 2), principally defined by shared variance of plasminogen and oxidized phospholipids on plasminogen. In a model including both factors, the thrombotic factor was associated with the higher risk of ASCVD events [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.45, 1.70], while the fibrinolytic factor was associated with the lower risk of ASCVD events (HR 0.76, 95% CI 0.70, 0.82), with estimated ASCVD free survival highest for low atherothrombotic Factor 1 and high atherothrombotic Factor 2.

Conclusion: Two atherothrombotic factors, one representative of thrombotic propensity and the other representative of fibrinolytic propensity, were significantly and complementarily associated with incident ASCVD events, remained significantly associated with incident ASCVD after controlling for traditional risk factors, and have promise for identifying patients at high ASCVD event risk specifically due to their atherothrombotic profile.
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http://dx.doi.org/10.1093/eurheartj/ehab600DOI Listing
September 2021

Neutralization of oxidized phospholipids attenuates age-associated bone loss in mice.

Aging Cell 2021 08 19;20(8):e13442. Epub 2021 Jul 19.

Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases and Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.

Oxidized phospholipids (OxPLs) are pro-inflammatory molecules that affect bone remodeling under physiological conditions. Transgenic expression of a single-chain variable fragment (scFv) of the antigen-binding domain of E06, an IgM natural antibody that recognizes the phosphocholine (PC) moiety of OxPLs, increases trabecular and cortical bone in adult male and female mice by increasing bone formation. OxPLs increase with age, while natural antibodies decrease. Age-related bone loss is associated with increased oxidative stress and lipid peroxidation and is characterized by a decline in osteoblast number and bone formation, raising the possibility that increased OxPLs, together with the decline of natural antibodies, contribute to age-related bone loss. We show here that transgenic expression of E06-scFv attenuated the age-associated loss of spinal, femoral, and total bone mineral density in both female and male mice aged up to 22 and 24 months, respectively. E06-scFv attenuated the age-associated decline in trabecular bone, but not cortical bone, and this effect was associated with an increase in osteoblasts and a decrease in osteoclasts. Furthermore, RNA-seq analysis showed that E06-scFv increased Wnt10b expression in vertebral bone in aged mice, indicating that blocking OxPLs increases Wnt signaling. Unlike age-related bone loss, E06-scFv did not attenuate the bone loss caused by estrogen deficiency or unloading in adult mice. These results demonstrate that OxPLs contribute to age-associated bone loss. Neutralization of OxPLs, therefore, is a promising therapeutic target for senile osteoporosis, as well as atherosclerosis and non-alcoholic steatohepatitis (NASH), two other conditions shown to be attenuated by E06-scFv in mice.
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http://dx.doi.org/10.1111/acel.13442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373359PMC
August 2021

Antisense Inhibition of Angiotensinogen With IONIS-AGT-L: Results of Phase 1 and Phase 2 Studies.

JACC Basic Transl Sci 2021 Jun 3;6(6):485-496. Epub 2021 May 3.

Ionis Pharmaceuticals, Carlsbad, California, USA.

Targeting angiotensinogen (AGT) may provide a novel approach to more optimally inhibit the renin-angiotensin-aldosterone system pathway. Double-blind, placebo-controlled clinical trials were performed in subjects with hypertension as monotherapy or as an add-on to angiotensin-converting enzyme inhibitors/angiotensin receptor blockers with IONIS-AGT-L versus placebo up to 2 months. IONIS-AGT-L was well tolerated with no significant changes in platelet count, potassium levels, or liver and renal function. IONIS-AGT-L significantly reduced AGT levels compared with placebo in all 3 studies. Although not powered for this endpoint, trends were noted in blood pressure reduction. In conclusion, IONIS-AGT-L significantly reduces AGT with a favorable safety, tolerability, and on-target profile. (A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx; NCT04083222; A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor Administered Subcutaneously to Hypertensive Subjects With Controlled Blood Pressure; NCT03714776; Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ionis AGT-LRx in Healthy Volunteers; NCT03101878).
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http://dx.doi.org/10.1016/j.jacbts.2021.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246029PMC
June 2021

Association of lipoprotein(a) with intrinsic and on-clopidogrel platelet reactivity.

J Thromb Thrombolysis 2021 Jul 2. Epub 2021 Jul 2.

Department of Cardiology and Angiology II, Medical Center, University of Freiburg, University Heart Center Freiburg-Bad Krozingen, Suedring 15, 79189, Bad Krozingen, Germany.

Lipoprotein(a) [Lp(a)] is an independent, genetically determined, and causal risk factor for cardiovascular disease. Laboratory data have suggested an interaction of Lp(a) with platelet function, potentially caused by its interaction with platelet receptors. So far, the potential association of Lp(a) with platelet activation and reactivity has not been proven in larger clinical cohorts. This study analyzed intrinsic platelet reactivity before loading with clopidogrel 600 mg and on-treatment platelet reactivity tested 24 h following loading in patients undergoing elective coronary angiography. Platelet reactivity was tested by optical aggregometry following stimulation with collagen or adenosine diphosphate as well as by flow cytometry. Lp(a) levels were directly measured in all patients from fresh samples. The present analysis included 1912 patients. Lp(a) levels ranged between 0 and 332 mg/dl. There was a significant association of rising levels of Lp(a) with a higher prevalence of a history of ischemic heart disease (p < 0.001) and more extensive coronary artery disease (p = 0.001). Results for intrinsic (p = 0.80) and on-clopidogrel platelet reactivity (p = 0.81) did not differ between quartiles of Lp(a) levels. Flow cytometry analyses of expression of different platelet surface proteins (CD41, CD62P or PAC-1) confirmed these findings. Correlation analyses of levels of Lp(a) with any of the tested platelet activation markers did not show any correlation. The present data do not support the hypothesis of an interaction of Lp(a) with platelet reactivity.
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http://dx.doi.org/10.1007/s11239-021-02515-2DOI Listing
July 2021

Elevated lipoprotein(a) and the risk of stroke in children, young adults, and the elderly.

Eur Heart J 2021 06;42(22):2197-2200

Division of Cardiovascular Sciences, University of California San Diego, La Jolla, CA, USA.

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http://dx.doi.org/10.1093/eurheartj/ehab251DOI Listing
June 2021

Prevalence and influence of LPA gene variants and isoform size on the Lp(a)-lowering effect of pelacarsen.

Atherosclerosis 2021 05 30;324:102-108. Epub 2021 Mar 30.

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

Background And Aims: Antisense oligonucleotides (ASOs) targeting LPA to lower lipoprotein(a) [Lp(a]] are in clinical trials. Patients have been recruited according to various Lp(a) thresholds, but the prevalence of LPA genetic variants and their effect on efficacy of these ASOs are not well described.

Methods: We analyzed data from 4 clinical trials of the ASO pelacarsen targeting apolipoprotein(a) that included 455 patients. Common LPA genetic variants rs10455872 and rs3798220, major and minor isoform size, and changes in Lp(a), LDL-C, apoB, OxPL-apoB and OxPL-apo(a) were analyzed according to categories of baseline Lp(a).

Results: The prevalence of carrier status for rs10455872 and rs3798220 combined ranged from 25.9% in patients with Lp(a) in the 75 - <125 nmol/L range to 77.1% at Lp(a) ≥375 nmol/L. The prevalence of homozygosity for rs3798220, rs10455872 and for double heterozygosity in category of Lp(a) ≥375 nmol/L was 6.3%, 14.6% and 12.5%, respectively. Isoform size decreased with increasing Lp(a) plasma levels, with 99.3% of patients with Lp(a) ≥175 nmol/L having ≤20 KIV repeats in the major isoform. The mean percent reduction from baseline in Lp(a), OxPL-apoB and OxPL-apo(a) in response to pelacarsen was not affected by the presence of rs10455872 and rs3798220, isoform size or baseline Lp(a) at all doses studied.

Conclusions: In patients randomized to Lp(a) lowering trials, LPA genetic variants are common, but a sizable proportion do not carry common variants associated with elevated Lp(a). In contrast, the major isoform size was almost uniformly ≤20 KIV repeats in patients with Lp(a) ≥175 nmol/L. The Lp(a) and OxPL lowering effects of pelacarsen were independent of both LPA genetic variants and isoform size.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.036DOI Listing
May 2021

Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.

Lancet Diabetes Endocrinol 2021 05 30;9(5):264-275. Epub 2021 Mar 30.

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

Background: Volanesorsen is an antisense oligonucleotide that targets hepatic apolipoprotein C-III synthesis and reduces plasma triglyceride concentration. The aim of this study was to explore the safety and efficacy of volanesorsen in patients with multifactorial chylomicronaemia syndrome.

Methods: The COMPASS trial was a randomised, placebo-controlled, double-blind, phase 3 study done at 38 international clinical sites in Canada, France, Germany, the Netherlands, UK, and USA. Eligible patients were aged 18 years or older with multifactorial severe hypertriglyceridaemia or familial chylomicronaemia syndrome, who had a BMI of 45 kg/m or less and fasting plasma triglyceride of 500 mg/dL or higher. Patients were randomly assigned (2:1) with an interactive response system using an allocation sequence and permuted block randomisation to receive subcutaneous volanesorsen (300 mg) or a matched volume of placebo (1·5 mL) once a week for 26 weeks. After 13 weeks of treatment, dosing was changed to 300 mg of volanesorsen or placebo every 2 weeks for all patients, except those who had completed 5 months or more of treatment as of May 27, 2016. Participants, investigators, sponsor personnel, and clinical research staff were all masked to the treatment assignments. The primary outcome was percentage change from baseline to 3 months in fasting triglyceride in the full analysis set (all patients who were randomly assigned and received at least one dose of study drug and had a baseline fasting triglyceride assessment). This trial is registered with ClinicalTrials.gov, NCT02300233 (completed).

Findings: Between Feb 5, 2015, and Jan 24, 2017, 408 patients were screened for eligibility. 294 were excluded and 114 randomly assigned to receive either volanesorsen (n=76) or placebo (n=38). One patient in the volanesorsen group discontinued before receiving the study drug. The total number of dropouts was 28 (four in the placebo group and 24 in the treatment group). Volanesorsen reduced mean plasma triglyceride concentration by 71·2% (95% CI -79·3 to -63·2) from baseline to 3 months compared with 0·9% (-13·9 to 12·2) in the placebo group (p<0·0001), representing a mean absolute reduction of fasting plasma triglycerides of 869 mg/dL (95% CI -1018 to -720; 9·82 mmol/L [-11·51 to -8·14]) in volanesorsen compared with an increase in placebo of 74 mg/dL (-138 to 285; 0·83 mmol/L [-1·56 to 3·22]; p<0·0001). In the key safety analysis, five adjudicated events of acute pancreatitis occurred during the study treatment period, all in three of 38 patients in the placebo group. The most common adverse events were related to tolerability and included injection-site reactions (average of 24% of all volanesorsen injections vs 0·2% of placebo injections), which were all mild or moderate. One participant in the volanesorsen group had a platelet count reduction to less than 50 000 per μL and one patient had serum sickness, both of which were regarded as serious adverse events.

Interpretation: Volanesorsen significantly reduced triglyceride concentrations in patients with multifactorial chlyomicronaemia and might reduce acute pancreatitis events in these patients.

Funding: Ionis Pharmaceuticals and Akcea Therapeutics.
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http://dx.doi.org/10.1016/S2213-8587(21)00046-2DOI Listing
May 2021

The Prolyl-tRNA Synthetase Inhibitor Halofuginone Inhibits SARS-CoV-2 Infection.

bioRxiv 2021 Mar 26. Epub 2021 Mar 26.

We identify the prolyl-tRNA synthetase (PRS) inhibitor halofuginone , a compound in clinical trials for anti-fibrotic and anti-inflammatory applications , as a potent inhibitor of SARS-CoV-2 infection and replication. The interaction of SARS-CoV-2 spike protein with cell surface heparan sulfate (HS) promotes viral entry . We find that halofuginone reduces HS biosynthesis, thereby reducing spike protein binding, SARS-CoV-2 pseudotyped virus, and authentic SARS-CoV-2 infection. Halofuginone also potently suppresses SARS-CoV-2 replication post-entry and is 1,000-fold more potent than Remdesivir . Inhibition of HS biosynthesis and SARS-CoV-2 infection depends on specific inhibition of PRS, possibly due to translational suppression of proline-rich proteins. We find that pp1a and pp1ab polyproteins of SARS-CoV-2, as well as several HS proteoglycans, are proline-rich, which may make them particularly vulnerable to halofuginone's translational suppression. Halofuginone is orally bioavailable, has been evaluated in a phase I clinical trial in humans and distributes to SARS-CoV-2 target organs, including the lung, making it a near-term clinical trial candidate for the treatment of COVID-19.
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http://dx.doi.org/10.1101/2021.03.22.436522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010724PMC
March 2021

Emerging RNA Therapeutics to Lower Blood Levels of Lp(a): JACC Focus Seminar 2/4.

J Am Coll Cardiol 2021 03;77(12):1576-1589

Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.

Lipoprotein(a) [Lp(a)] has risen to the level of an accepted cardiovascular disease risk factor, but final proof of causality awaits a randomized trial of Lp(a) lowering. Inhibiting apolipoprotein(a) production in the hepatocyte with ribonucleic acid therapeutics has emerged as an elegant and effective solution to reduce plasma Lp(a) levels. Phase 2 clinical trials have shown that the antisense oligonucleotide pelacarsen reduced mean Lp(a) levels by 80%, allowing 98% of subjects to reach on-treatment levels of <125 nmol/l (∼50 mg/dl). The phase 3 Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering With TQJ230 on Major Cardiovascular Events in Patients With CVD) outcomes trial is currently enrolling approximately 7,680 patients with history of myocardial infarction, ischemic stroke, and symptomatic peripheral arterial disease and controlled low-density lipoprotein cholesterol to pelacarsen versus placebo. The co-primary endpoints are major adverse cardiovascular events in subjects with Lp(a) >70 mg/dl and >90 mg/dl, in which either of the two being positive will lead to a successful trial. Additional ribonucleic acid-targeted therapies to lower Lp(a) are in preclinical and clinical development. The testing of the Lp(a) hypothesis will provide proof whether Lp(a)-mediated risk can be abolished by potent Lp(a) lowering.
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http://dx.doi.org/10.1016/j.jacc.2021.01.051DOI Listing
March 2021

Design and Rationale of the Global Phase 3 NEURO-TTRansform Study of Antisense Oligonucleotide AKCEA-TTR-L (ION-682884-CS3) in Hereditary Transthyretin-Mediated Amyloid Polyneuropathy.

Neurol Ther 2021 Jun 26;10(1):375-389. Epub 2021 Feb 26.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

Introduction: AKCEA-TTR-L is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-L shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-L is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-L is safe and efficacious, with the aim of improving neurologic function and quality of life in hATTR-PN patients.

Methods/design: Approximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-L 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-L 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-L through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-L arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life-Diabetic Neuropathy questionnaire.

Conclusion: NEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-L to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN.

Trial Registration: The study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10).
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http://dx.doi.org/10.1007/s40120-021-00235-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140170PMC
June 2021

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

J Lipid Res 2021 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

Glucose Control in Patients Undergoing PCI: What Is the Optimal HbA for Long-Term Outcomes?

JACC Cardiovasc Interv 2021 02;14(4):398-400

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

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http://dx.doi.org/10.1016/j.jcin.2020.11.038DOI Listing
February 2021

Effect of bariatric surgery on plasma levels of oxidised phospholipids, biomarkers of oxidised LDL and lipoprotein(a).

J Clin Lipidol 2021 Mar-Apr;15(2):320-331. Epub 2020 Dec 11.

Department of Medicine, Manchester University NHS Foundation Trust, Manchester, UK; Lipid Research Group, Division of Medical Sciences, The University of Manchester, Manchester, UK. Electronic address:

Background: Obesity is associated with adverse cardiovascular outcomes and this is improved following bariatric surgery. Oxidised phospholipids (OxPL) are thought to reflect the pro-inflammatory effects of lipoprotein(a) [Lp(a)], and both are independent predictors of cardiovascular disease.

Objective: Our study sought to determine the impact of bariatric surgery on OxPL, biomarkers of oxidised LDL (OxLDL) and Lp(a).

Methods: This is a prospective, observational study of 59 patients with severe obesity undergoing bariatric surgery. Blood samples were obtained prior to surgery and at 6 and 12 months after. Sixteen patients attending the tertiary medical weight management clinic at the same centre were also recruited for comparison. Lipid and metabolic blood parameters, OxLDL, OxPL on apolipoprotein B-100 (OxPL-apoB), IgG and IgM autoantibodies to MDA-LDL, IgG and IgM apoB-immune complexes and Lp(a) were measured.

Results: Reduction in body mass index (BMI) was significant following bariatric surgery, from median 48 kg/m at baseline to 37 kg/m at 6 months and 33 kg/m at 12 months. OxPL-apoB levels decreased significantly at 12 months following surgery [5.0 (3.2-7.4) to 3.8 (3.0-5.5) nM, p = 0.001], while contrastingly, Lp(a) increased significantly [10.2 (3.8-31.9) to 16.9 (4.9-38.6) mg/dl, p = 0.002]. There were significant post-surgical decreases in IgG and IgM biomarkers, particularly at 12 months, while OxLDL remained unchanged.

Conclusions: Bariatric surgery results in a significant increase in Lp(a) but reductions in OxPL-apoB and other biomarkers of oxidised lipoproteins, suggesting increased synthetic capacity and reduced oxidative stress. These biomarkers might be clinically useful to monitor physiological effects of weight loss interventions.
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http://dx.doi.org/10.1016/j.jacl.2020.12.002DOI Listing
December 2021

Intracellular AIBP (Apolipoprotein A-I Binding Protein) Regulates Oxidized LDL (Low-Density Lipoprotein)-Induced Mitophagy in Macrophages.

Arterioscler Thromb Vasc Biol 2021 02 24;41(2):e82-e96. Epub 2020 Dec 24.

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

Objective: Atherosclerotic lesions are often characterized by accumulation of OxLDL (oxidized low-density lipoprotein), which is associated with vascular inflammation and lesion vulnerability to rupture. Extracellular AIBP (apolipoprotein A-I binding protein; encoded by gene), when secreted, promotes cholesterol efflux and regulates lipid rafts dynamics, but its role as an intracellular protein in mammalian cells remains unknown. The aim of this work was to determine the function of intracellular AIBP in macrophages exposed to OxLDL and in atherosclerotic lesions. Approach and Results: Using a novel monoclonal antibody against human and mouse AIBP, which are highly homologous, we demonstrated robust AIBP expression in human and mouse atherosclerotic lesions. We observed significantly reduced autophagy in bone marrow-derived macrophages, isolated from compared with wild-type mice, which were exposed to OxLDL. In atherosclerotic lesions from mice subjected to knockdown and fed a Western diet, autophagy was reduced, whereas apoptosis was increased, when compared with that in wild-type mice. AIBP expression was necessary for efficient control of reactive oxygen species and cell death and for mitochondria quality control in macrophages exposed to OxLDL. Mitochondria-localized AIBP, via its N-terminal domain, associated with E3 ubiquitin-protein ligase PARK2 (Parkin), MFN (mitofusin)1, and MFN2, but not BNIP3 (Bcl2/adenovirus E1B 19-kDa-interacting protein-3), and regulated ubiquitination of MFN1 and MFN2, key components of mitophagy.

Conclusions: These data suggest that intracellular AIBP is a new regulator of autophagy in macrophages. Mitochondria-localized AIBP augments mitophagy and participates in mitochondria quality control, protecting macrophages against cell death in the context of atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.120.315485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105271PMC
February 2021

Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data.

ESC Heart Fail 2021 02 7;8(1):652-661. Epub 2020 Dec 7.

Ionis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA, 92010, USA.

Aims: Amyloidogenic transthyretin (ATTR) amyloidosis is a fatal disease characterized by progressive cardiomyopathy and/or polyneuropathy. AKCEA-TTR-L (ION-682884) is a ligand-conjugated antisense drug designed for receptor-mediated uptake by hepatocytes, the primary source of circulating transthyretin (TTR). Enhanced delivery of the antisense pharmacophore is expected to increase drug potency and support lower, less frequent dosing in treatment.

Methods And Results: AKCEA-TTR-L demonstrated an approximate 50-fold and 30-fold increase in potency compared with the unconjugated antisense drug, inotersen, in human hepatocyte cell culture and mice expressing a mutated human genomic TTR sequence, respectively. This increase in potency was supported by a preferential distribution of AKCEA-TTR-L to liver hepatocytes in the transgenic hTTR mouse model. A randomized, placebo-controlled, phase 1 study was conducted to evaluate AKCEA-TTR-L in healthy volunteers (ClinicalTrials.gov: NCT03728634). Eligible participants were assigned to one of three multiple-dose cohorts (45, 60, and 90 mg) or a single-dose cohort (120 mg), and then randomized 10:2 (active : placebo) to receive a total of 4 SC doses (Day 1, 29, 57, and 85) in the multiple-dose cohorts or 1 SC dose in the single-dose cohort. The primary endpoint was safety and tolerability; pharmacokinetics and pharmacodynamics were secondary endpoints. All randomized participants completed treatment. No serious adverse events were reported. In the multiple-dose cohorts, AKCEA-TTR-L reduced TTR levels from baseline to 2 weeks after the last dose of 45, 60, or 90 mg by a mean (SD) of -85.7% (8.0), -90.5% (7.4), and -93.8% (3.4), compared with -5.9% (14.0) for pooled placebo (P < 0.001). A maximum mean (SD) reduction in TTR levels of -86.3% (6.5) from baseline was achieved after a single dose of 120 mg AKCEA-TTR-L .

Conclusions: These findings suggest an improved safety and tolerability profile with the increase in potency achieved by productive receptor-mediated uptake of AKCEA-TTR-L by hepatocytes and supports further development of AKCEA-TTR-L for the treatment of ATTR polyneuropathy and cardiomyopathy.
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http://dx.doi.org/10.1002/ehf2.13154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835591PMC
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

microRNA-483 ameliorates hypercholesterolemia by inhibiting PCSK9 production.

JCI Insight 2020 12 3;5(23). Epub 2020 Dec 3.

Division of Cardiology and.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects cholesterol homeostasis by targeting hepatic LDL receptor (LDLR) for lysosomal degradation. Clinically, PCSK9 inhibitors effectively reduce LDL-cholesterol (LDL-C) levels and the incidence of cardiovascular events. Because microRNAs (miRs) are integral regulators of cholesterol homeostasis, we investigated the involvement of miR-483 in regulating LDL-C metabolism. Using in silico analysis, we predicted that miR-483-5p targets the 3'-UTR of PCSK9 mRNA. In HepG2 cells, miR-483-5p targeted the PCSK9 3'-UTR, leading to decreased PCSK9 protein and mRNA expression, increased LDLR expression, and enhanced LDL-C uptake. In hyperlipidemic mice and humans, serum levels of total cholesterol and LDL-C were inversely correlated with miR-483-5p levels. In mice, hepatic miR-483 overexpression increased LDLR levels by targeting Pcsk9, with a significant reduction in plasma total cholesterol and LDL-C levels. Mechanistically, the cholesterol-lowering effect of miR-483-5p was significant in mice receiving AAV8 PCSK9-3'-UTR but not Ldlr-knockout mice or mice receiving AAV8 PCSK9-3'-UTR (ΔBS) with the miR-483-5p targeting site deleted. Thus, exogenously administered miR-483 or similarly optimized compounds have potential to ameliorate hypercholesterolemia.
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http://dx.doi.org/10.1172/jci.insight.143812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714402PMC
December 2020

Genome-Wide Association Study Highlights as a Novel Locus for Lipoprotein(a) Levels-Brief Report.

Arterioscler Thromb Vasc Biol 2021 01 29;41(1):458-464. Epub 2020 Oct 29.

Division of Experimental Medicine (M.H., H.Y.C., G.T., J.C.E.), McGill University, Montreal, Quebec.

Objective: Lp(a) (lipoprotein[a]) is an independent risk factor for cardiovascular diseases and plasma levels are primarily determined by variation at the locus. We performed a genome-wide association study in the UK Biobank to determine whether additional loci influence Lp(a) levels. Approach and Results: We included 293 274 White British individuals in the discovery analysis. Approximately 93 095 623 variants were tested for association with natural log-transformed Lp(a) levels using linear regression models adjusted for age, sex, genotype batch, and 20 principal components of genetic ancestry. After quality control, 131 independent variants were associated at genome-wide significance ≤5×10). In addition to validating previous associations at , , and , we identified a novel variant at the locus, encoding β2GPI (beta2-glycoprotein I). The variant rs8178824 was associated with increased Lp(a) levels (β [95% CI] [ln nmol/L], 0.064 [0.047-0.081]; =2.8×10) and demonstrated a stronger effect after adjustment for variation at the locus (β [95% CI] [ln nmol/L], 0.089 [0.076-0.10]; =3.8×10). This association was replicated in a meta-analysis of 5465 European-ancestry individuals from the Framingham Offspring Study and Multi-Ethnic Study of Atherosclerosis (β [95% CI] [ln mg/dL], 0.16 [0.044-0.28]; =0.0071).

Conclusions: In a large-scale genome-wide association study of Lp(a) levels, we identified as a novel locus for Lp(a) in individuals of European ancestry. Additional studies are needed to determine the precise role of β2GPI in influencing Lp(a) levels as well as its potential as a therapeutic target.
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http://dx.doi.org/10.1161/ATVBAHA.120.314965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769958PMC
January 2021

Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial.

Eur Heart J 2020 11;41(44):4245-4255

Division of Cardiology, University of Colorado School of Medicine, Box B130, Aurora, CO 80045, USA.

Aims: Lipoprotein(a) concentration is associated with first cardiovascular events in clinical trials. It is unknown if this relationship holds for total (first and subsequent) events. In the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab reduced lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), and cardiovascular events compared with placebo. This post hoc analysis determined whether baseline levels and alirocumab-induced changes in lipoprotein(a) and LDL-C [corrected for lipoprotein(a) cholesterol] independently predicted total cardiovascular events.

Methods And Results: Cardiovascular events included cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina or heart failure, ischaemia-driven coronary revascularization, peripheral artery disease events, and venous thromboembolism. Proportional hazards models estimated relationships between baseline lipoprotein(a) and total cardiovascular events in the placebo group, effects of alirocumab treatment on total cardiovascular events by baseline lipoprotein(a), and relationships between lipoprotein(a) reduction with alirocumab and subsequent risk of total cardiovascular events. Baseline lipoprotein(a) predicted total cardiovascular events with placebo, while higher baseline lipoprotein(a) levels were associated with greater reduction in total cardiovascular events with alirocumab (hazard ratio Ptrend = 0.045). Alirocumab-induced reductions in lipoprotein(a) (median -5.0 [-13.6, 0] mg/dL) and corrected LDL-C (median -51.3 [-67.1, -34.0] mg/dL) independently predicted lower risk of total cardiovascular events. Each 5-mg/dL reduction in lipoprotein(a) predicted a 2.5% relative reduction in cardiovascular events.

Conclusion: Baseline lipoprotein(a) predicted the risk of total cardiovascular events and risk reduction by alirocumab. Lipoprotein(a) lowering contributed independently to cardiovascular event reduction, supporting the concept of lipoprotein(a) as a treatment target after ACS.
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http://dx.doi.org/10.1093/eurheartj/ehaa649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724642PMC
November 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

A Neutralizing Antibody Targeting Oxidized Phospholipids Promotes Bone Anabolism in Chow-Fed Young Adult Mice.

J Bone Miner Res 2021 01 29;36(1):170-185. Epub 2020 Sep 29.

Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases and Center for Musculoskeletal Disease Research, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.

Oxidized phospholipids containing phosphocholine (OxPL) are pro-inflammatory lipid peroxidation products that bind to scavenger receptors (SRs), such as Scarb1, and toll-like receptors (TLRs). Excessive OxPL, as found in oxidized low-density lipoprotein (OxLDL), overwhelm these defense mechanisms and become pathogenic in atherosclerosis, nonalcoholic steatohepatitis (NASH), and osteoporosis. We previously reported that the innate IgM natural antibody E06 binds to OxPL and neutralizes their deleterious effects; expression of the single-chain (scFv) form of the antigen-binding domain of E06 (E06-scFv) as a transgene increases trabecular bone in male mice. We show herein that E06-scFv increases trabecular and cortical bone in female and male mice by increasing bone formation and decreasing osteoblast apoptosis in vivo. Homozygous E06-scFv mice have higher bone mass than hemizygous, showing a dose effect of the transgene. To investigate how OxPL restrain bone formation under physiologic conditions, we measured the levels of SRs and TLRs that bind OxPL. We found that osteoblastic cells primarily express Scarb1. Moreover, OxLDL-induced apoptosis and reduced differentiation were prevented in bone marrow-derived or calvaria-derived osteoblasts from Scarb1 knockout mice. Because Scarb1-deficient mice are reported to have high bone mass, our results suggest that E06 may promote bone anabolism in healthy young mice, at least in part, by neutralizing OxPL, which in turn promote Scarb1-mediated apoptosis of osteoblasts or osteoblast precursors. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..
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http://dx.doi.org/10.1002/jbmr.4173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855899PMC
January 2021

Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia.

Eur Heart J 2020 10;41(40):3936-3945

Akcea Therapeutics, Inc, Boston, MA, USA.

Aims: Loss-of-function mutations in ANGPTL3 are associated with beneficial effects on lipid and glucose metabolism and reduced risk of coronary artery disease. Vupanorsen (AKCEA-ANGPTL3-L Rx ) is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits angiopoietin-like 3 (ANGPTL3) protein synthesis.

Methods And Results: This was a double-blind, placebo-controlled, dose-ranging, Phase 2 study. Patients (N =105) with fasting triglycerides >150 mg/dL (>1.7 mmol/L), type 2 diabetes, and hepatic steatosis were treated for 6 months with 40 or 80 mg every 4 weeks (Q4W), or 20 mg every week (QW) of vupanorsen, or placebo given subcutaneously. The primary efficacy endpoint was per cent change in fasting triglycerides from baseline at 6 months. Median baseline triglycerides were 2.84 mmol/L (252 mg/dL). Significant reductions in triglycerides of 36%, 53%, 47%, and in ANGPTL3 of 41%, 59%, 56%, were observed in the 40 mg Q4W, 80 mg Q4W, and 20 mg QW groups, respectively, compared with 16% reduction in triglycerides and 8% increase in ANGPTL3 in placebo. Compared with placebo, vupanorsen 80 mg Q4W reduced apolipoprotein C-III (58%), remnant cholesterol (38%), total cholesterol (19%), non-high-density lipoprotein cholesterol (HDL-C; 18%), HDL-C (24%), and apolipoprotein B (9%). There was no improvement in glycaemic parameters, or hepatic fat fraction. Treatment with vupanorsen was not associated with clinically significant changes in platelet counts, and the most common adverse events were those at the injection site, which were generally mild.

Conclusion: Vupanorsen results in a favourable lipid/lipoprotein profile and provides a potential strategy for residual cardiovascular risk reduction.
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http://dx.doi.org/10.1093/eurheartj/ehaa689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750927PMC
October 2020

Lipoprotein(a) and Its Potential Association with Thrombosis and Inflammation in COVID-19: a Testable Hypothesis.

Curr Atheroscler Rep 2020 07 25;22(9):48. Epub 2020 Jul 25.

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

Purpose Of Review: The COVID-19 pandemic has infected over > 11 million as of today people worldwide and is associated with significant cardiovascular manifestations, particularly in subjects with preexisting comorbidities and cardiovascular risk factors. Recently, a predisposition for arterial and venous thromboses has been reported in COVID-19 infection. We hypothesize that besides conventional risk factors, subjects with elevated lipoprotein(a) (Lp(a)) may have a particularly high risk of developing cardiovascular complications.

Recent Findings: The Lp(a) molecule has the propensity for inhibiting endogenous fibrinolysis through its apolipoprotein(a) component and for enhancing proinflammatory effects such as through its content of oxidized phospholipids. The LPA gene contains an interleukin-6 (IL-6) response element that may induce an acute phase-type increase in Lp(a) levels following a cytokine storm from COVID-19. Thus, subjects with either baseline elevated Lp(a) or those who have an increase following COVID-19 infection, or both, may be at very high risk of developing thromboses. Elevated Lp(a) may also lead to acute destabilization of preexisting but quiescent atherosclerotic plaques, which might induce acute myocardial infarction and stroke. Ongoing studies with IL-6 antagonists may be informative in understanding this relationship, and registries are being initiated to measure Lp(a) in subjects infected with COVID-19. If indeed an association is suggestive of being causal, consideration can be given to systematic testing of Lp(a) and prophylactic systemic anticoagulation in infected inpatients. Therapeutic lipid apheresis and pharmacotherapy for the reduction of Lp(a) levels may minimize thrombogenic potential and proinflammatory effects. We propose studies to test the hypothesis that Lp(a) may contribute to cardiovascular complications of COVID-19.
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http://dx.doi.org/10.1007/s11883-020-00867-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381416PMC
July 2020
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