Lower Lp Research Articles

Lipoprotein(a)-apheresis in the light of new drug developments

Elevated levels of lipoprotein(a) (Lp(a)) contribute to the risk of early and severe cardiovascular disease (CVD). Recently <50 mg/dl was recommended as the desirable level for clinical use and decision making. All established medical therapies to lower cholesterol levels have no impact on lowering Lp(a) except niacin which is all too often poorly tolerated and not obtainable everywhere. Lipoprotein apheresis is an extracorporeal treatment to lower levels of Lp(a) significantly by > 60%. In some countries it is recommended in very high risk patients with early or progressive CVD. Retrospective data indicate that regular apheresis reduces cardiovascular events, which was substantiated by a recent prospective observational trial. Apheresis is very well tolerated with very few side effects, but it is expensive, time consuming, and offered by specialised centres only.To improve the overall treatment new drug therapies are required. Some of the recently approved lipid modifying drugs lower Lp(a) in addition to LDL-cholesterol: Mipomersen ∼ 25%, CETP-inhibitors ∼ 50%, PCSK9-inhibitors ∼ 30%. If the Lp(a) lowering effect contributes to the expected reduction of CVD events has to be shown in the future. The apo(a) antisense oligonucleotide is the only approach to specifically lower Lp(a). A phase 1 trial showed a decrease in a dose dependant manner (up to 88.8%) in healthy volunteers.Despite the lack of prospective randomised trials apheresis these days remains the standard of care in patients with elevated Lp(a) and severe CVD.

Lipoprotein (a) Evolution: Possible Benefits and Harm. Genetic and Non-Genetic Factors Influencing its Plasma Levels.

The limited distribution of lipoprotein (a) (Lp(a)) to humans, Old World primates and to the European hedgehog, has raised considerable interest and speculation regarding its possible physiological role. Lp(a) has variable circulating concentrations (<0.1 - >100 mg/ml) which are highly genetically determined in humans. These characteristics gave rise to several theories concerning the origins and evolution of Lp(a). Lp(a) has a protective role after injury since Lp(a) particles bind to macrophages and platelets membrane receptors, leading to fibrin activation and injury healing. On the other hand, Lp(a) seems to be implicated in the formation of atheromatic plaques but also in cerebrovascular events and stenosis of the aortic valve. The main genetic factor determining plasma Lp(a) levels is the Lp(a) gene (LPA). Most Caucasian people have normal plasma Lp(a) concentrations, but there is important distribution variation according to race. Women seem to have increased Lp(a) levels compared with men, while diabetes mellitus type 2 favours lower plasma Lp(a) levels. Nutrition, hormones and several drugs may also influence circulating Lp(a) levels.

Lipoprotein(a) and the risk of cardiovascular disease in the European population: results from the BiomarCaRE consortium.

AimsAs promising compounds to lower Lipoprotein(a) (Lp(a)) are emerging, the need for a precise characterization and comparability of the Lp(a)-associated cardiovascular risk is increasing. Therefore, we aimed to evaluate the distribution of Lp(a) concentrations across the European population, to characterize the association with cardiovascular outcomes and to provide high comparability of the Lp(a)-associated cardiovascular risk by use of centrally determined Lp(a) concentrations.Methods and resultsBased on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project, we analysed data of 56 804 participants from 7 prospective population-based cohorts across Europe with a maximum follow-up of 24 years. All Lp(a) measurements were performed in the central BiomarCaRE laboratory (Biokit Quantia Lp(a)-Test; Abbott Diagnostics). The three endpoints considered were incident major coronary events (MCE), incident cardiovascular disease (CVD) events, and total mortality. We found lower Lp(a) levels in Northern European cohorts (median 4.9 mg/dL) compared to central (median 7.9 mg/dL) and Southern European cohorts (10.9 mg/dL) (Jonckheere–Terpstra test P < 0.001). Kaplan–Meier curves showed the highest event rate of MCE and CVD events for Lp(a) levels ≥90th percentile (log-rank test: P < 0.001 for MCE and CVD). Cox regression models adjusted for age, sex, and cardiovascular risk factors revealed a significant association of Lp(a) levels with MCE and CVD with a hazard ratio (HR) of 1.30 for MCE [95% confidence interval (CI) 1.15‒1.46] and of 1.25 for CVD (95% CI 1.12‒1.39) for Lp(a) levels in the 67‒89th percentile and a HR of 1.49 for MCE (95% CI 1.29‒1.73) and of 1.44 for CVD (95% CI 1.25‒1.65) for Lp(a) levels ≥ 90th percentile vs. Lp(a) levels in the lowest third (P < 0.001 for all). There was no significant association between Lp(a) levels and total mortality. Subgroup analysis for a continuous version of cube root transformed Lp(a) identified the highest Lp(a)-associated risk in individuals with diabetes [HR for MCE 1.31 (95% CI 1.15‒1.50)] and for CVD 1.22 (95% CI 1.08‒1.38) compared to those without diabetes [HR for MCE 1.15 (95% CI 1.08‒1.21; HR for CVD 1.13 (1.07–1.19)] while no difference of the Lp(a)- associated risk were seen for other cardiovascular high risk states. The addition of Lp(a) levels to a prognostic model for MCE and CVD revealed only a marginal but significant C-index discrimination measure increase (0.001 for MCE and CVD; P < 0.05) and net reclassification improvement (0.010 for MCE and 0.011 for CVD).ConclusionIn this large dataset on harmonized Lp(a) determination, we observed regional differences within the European population. Elevated Lp(a) was robustly associated with an increased risk for MCE and CVD in particular among individuals with diabetes. These results may lead to better identification of target populations who might benefit from future Lp(a)-lowering therapies.

Inverse association of lipoprotein (a) with markers of insulin resistance in dyslipidemic subjects.

Lipoprotein (a) [Lp(a)] is an LDL-like particle that contains an apolipoprotein B100 molecule covalently bound to a plasminogen-like glycoprotein, apolipoprotein (a) [apo(a)]. Epidemiological evidence supports a direct and causal association between Lp(a) levels and coronary risk. On the contrary, a few prospective findings demonstrate inverse association of Lp(a) levels with risk of type 2 diabetes (T2DM). The aim of our study was to evaluate the association of Lp(a) with indicators of insulin resistance (IR) and metabolic syndrome (MS), which precede development of T2DM. We enrolled 607 asymptomatic dyslipidemic subjects (295 men and 312 women, mean age 45.6+/-14.0 years) into our cross-sectional study. Lp(a) concentrations correlated inversely with TG, AIP, insulin, HOMA, C-peptide, BMI, waist circumference, and number of MS components (p<0.01 for all). Subjects with MS had significantly lower Lp(a) concentrations in comparison with those without the presence of this phenotype (p<0.0001). Serum concentrations of Lp(a) in the lower (1(th)-3(rd)) quartiles of insulin and HOMA were significantly higher than in the 4(th) quartile of these insulin resistance markers (p<0.001). Odds ratios of having increased markers of IR (TG, HOMA) and MS in top quartile of Lp(a) also indicate inverse association of Lp(a) with IR. The results of our study support an inverse association of Lp(a) levels with IR and MS that precedes overt T2DM diagnosis.

Discordant response of low-density lipoprotein cholesterol and lipoprotein(a) levels to monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9

Clinical trials testing proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have demonstrated an unanticipated but significant lipoprotein (a) (Lp(a))-lowering effect, on the order of 25% to 30%. Although the 50% to 60% reduction in low-density lipoprotein (LDL)-cholesterol (LDL-C) achieved by PCSK9i is mediated through its effect on LDL receptor (LDLR) preservation, the mechanism for Lp(a) lowering is unknown. We sought to characterize the degree of concordance between LDL-C and Lp(a) lowering because of PCSK9i in a standard of care patient cohort. Participants were selected from our Center for Preventive Cardiology, an outpatient referral center in a tertiary academic medical center. Subjects were included in this study if they had (1) at least 1 measurement of LDL-C and Lp(a) before and after initiation of the PCSK9i; (2) baseline Lp(a)>10mg/dL; and (3) continued adherence to PCSK9i therapy. They were excluded if (1)they were undergoing LDL apheresis; (2) pre- or post-PCSK9i LDL-C or Lp(a) laboratory values were censored; or (3) subjects discontinued other lipid-modifying therapies. In total, 103 subjects were identified as taking a PCSK9i and 26 metall inclusion and exclusion criteria. Concordant response to therapy was defined as an LDL-C reduction >35% and an Lp(a) reduction >10%. The cohort consisted of 26 subjects (15 females, 11 males, mean age 63±12years). Baseline mean LDL-C and median Lp(a) levels were 167.4±72mg/dL and 81mg/dL (interquartile range 38-136mg/dL), respectively. The average percent reductions in LDL-C and Lp(a) were 52.8% (47.0-58.6) and 20.2% (12.2-28.1). The correlation between %LDL and %Lp(a) reduction was moderate, with a Spearman's correlation of 0.56 (P<.01). All subjects except for 1 had a protocol-appropriate LDL-C response to therapy. However, only 16 of the 26 (62%; 95% confidence interval 41%-82%) subjects had a protocol-concordant Lp(a) response. Although some subjects demonstrated negligible Lp(a) reduction associated with PCSK9i, there were some whose Lp(a) decreased as much as 60%. In this standard-of-care setting, we demonstrate moderate correlation but large discordance (∼40%) in these 2 lipid fractions in response to PCSK9i. The results suggest that pathways beyond the LDLR are responsible for Lp(a) lowering and indicate that PCSK9i have the potential to significantly lower Lp(a) in select patients, although confirmation in larger multicenter studies is required.

Lipoprotein(a): the revenant.

In the mid-1990s, the days of lipoprotein(a) [Lp(a)] were numbered and many people would not have placed a bet on this lipid particle making it to the next century. However, genetic studies brought Lp(a) back to the front-stage after a Mendelian randomization approach used for the first time provided strong support for a causal role of high Lp(a) concentrations in cardiovascular disease and later also for aortic valve stenosis. This encouraged the use of therapeutic interventions to lower Lp(a) as well numerous drug developments, although these approaches mainly targeted LDL cholesterol, while the Lp(a)-lowering effect was only a 'side-effect'. Several drug developments did show a potent Lp(a)-lowering effect but did not make it to endpoint studies, mainly for safety reasons. Currently, three therapeutic approaches are either already in place or look highly promising: (i) lipid apheresis (specific or unspecific for Lp(a)) markedly decreases Lp(a) concentrations as well as cardiovascular endpoints; (ii) PCSK9 inhibitors which, besides lowering LDL cholesterol also decrease Lp(a) by roughly 30%; and (iii) antisense therapy targeting apolipoprotein(a) which has shown to specifically lower Lp(a) concentrations by up to 90% in phase 1 and 2 trials without influencing other lipids. Until the results of phase 3 outcome studies are available for antisense therapy, we will have to exercise patience, but with optimism since never before have we had the tools we have now to prove Koch's extrapolated postulate that lowering high Lp(a) concentrations might be protective against cardiovascular disease.

Hyperlipoproteinaemia(a) \u2013 apheresis and emerging therapies

A high level of lipoprotein(a) (Lp(a)) is recognized as an independent and additional cardiovascular risk factor contributing to the risk of early onset and progressive course of cardiovascular disease (CVD). All lipid lowering medications in use mainly lower low density lipoprotein-cholesterol (LDL-c) with no or limited effect on levels of Lp(a). Niacin, the only component lowering Lp(a), is firstly often poorly tolerated and secondly not available anymore in many countries. A level of <50 mg/dl was recommended recently as the cut off level for clinical use and decision making. Since lipoprotein apheresis (LA) lowers not only LDL-c but also Lp(a) significantly, its use is recommended in some countries in very high-risk patients with early or progressive CVD. Retrospective analyses show that regular LA improves the course of CVD. This is supported by a recent prospective observational trial and data of the German Lipoprotein Apheresis Registry. Despite many treatment options, all too often it is not possible to reduce LDL-c levels to target and to reduce Lp(a) levels sustainably at all. Therefore, new drug therapies are awaited. Some of the lipid modifying drugs in development lower Lp(a) to some extent in addition to LDL-c; the only specific approach is the apoprotein(a) antisense oligonucleotide. Currently LA is the standard of care as a last resort treatment in high-risk patients with elevated Lp(a) and severe CVD despite optimal control of all other cardiovascular risk factors.

Prevention of cardiovascular complications in patients with Lp(a)-hyperlipoproteinemia and progressive cardiovascular disease by long-term lipoprotein apheresis according to German national guidelines

Lipoprotein(a) (Lp(a)) is an independent cardiovascular risk factor playing a causal role for atherosclerotic cardiovascular disease (CVD). Lipoprotein apheresis (LA) is a safe well-tolerated outpatient treatment to lower LDL-C and Lp(a) by 60–70%, and is the ultimate escalating therapeutic option in patients with hyperlipoproteinemias (HLP) involving LDL particles. Major therapeutic effect of LA is preventing cardiovascular events. Lp(a)-HLP associated with progressive CVD has been approved as indication for regular LA in Germany since 2008. The Pro(a)LiFe-study investigated with a prospective multicenter design the long-term preventive effect of LA on incidence rates of cardiovascular events prospectively over a period of 5 years in 170 consecutive patients who commenced regular LA. During a median period of 4.7 years of the pre-LA period, Lp(a) associated progressive CVD became apparent. Apolipoprotein(a) (apo(a)) isoforms and polymorphisms at the apo(a) gene (LPA) were analyzed to assess hypothetical clinical correlations. 154 patients (90.6%) completed 5‑years follow-up. Significant decline of the mean annual major adverse cardiac event (MACE) rate was observed from 0.41 ± 0.45 two years prior to regular LA to 0.06 ± 0.11 during 5 years with regular LA (p < 0.0001). 95.3% of patients expressed at least one small apo(a) isoform. Calculation of isoform specific concentrations allowed to confirm the equivalence of 60 mg/dl or 120 nmol/l as Lp(a) thresholds of the German LA guideline. Results of 5 years prospective follow-up confirmed that LA has a lasting effect on prevention of cardiovascular events in patients with Lp(a)-HLP and afore progressive CVD.

Comparison of the effects of fibrates versus statins on plasma lipoprotein(a) concentrations: a systematic review and meta-analysis of head-to-head randomized controlled trials

BackgroundRaised plasma lipoprotein(a) (Lp(a)) concentration is an independent and causal risk factor for atherosclerotic cardiovascular disease. Several types of pharmacological approaches are under evaluation for their potential to reduce plasma Lp(a) levels. There is suggestive evidence that statins and fibrates, two frequently employed lipid-lowering drugs, can lower plasma Lp(a). The present study aims to compare the efficacy of fibrates and statins in reducing plasma concentrations of Lp(a) using a meta-analysis of randomized head-to-head trials.MethodsMedline and Scopus databases were searched to identify randomized head-to-head comparative trials investigating the efficacy of fibrates versus statins in reducing plasma Lp(a) levels. Meta-analysis was performed using a random-effects model, with inverse variance weighted mean differences (WMDs) and 95% confidence intervals (CIs) as summary statistics. The impact of putative confounders on the estimated effect size was explored using random effects meta-regression.ResultsSixteen head-to-head comparative trials with a total of 1388 subjects met the eligibility criteria and were selected for this meta-analysis. Meta-analysis revealed a significantly greater effect of fibrates versus statins in reducing plasma Lp(a) concentrations (WMD, –2.70 mg/dL; 95% CI, –4.56 to –0.84; P = 0.004). Combination therapy with fibrates and statins had a significantly greater effect compared with statin monotherapy (WMD, –1.60 mg/dL; 95% CI, –2.93 to –0.26; P = 0.019) but not fibrate monotherapy (WMD, –1.76 mg/dL; 95% CI, –5.44 to +1.92; P = 0.349) in reducing plasma Lp(a) concentrations. The impact of fibrates versus statins in reducing plasma Lp(a) concentrations was not found to be significantly associated with treatment duration (P = 0.788).ConclusionsFibrates have a significantly greater effect in reducing plasma Lp(a) concentrations than statins. Addition of fibrates to statins can enhance the Lp(a)-lowering effect of statins.

Effect of oral supplementation with different energy boosters in newborn piglets on pre-weaning mortality, growth and serological levels of IGF-I and IgG.

Oral supplements are commonly used in commercial herds to improve energy status and passive immune acquisition of newborn piglets. However, there is little scientific evidence on the efficacy of oral supplements for piglets. The objective of this experiment was to study the effects of 2 oral supplementation products on piglet pre-weaning mortality and growth. A total of 62 litters (749 piglets) were distributed according to the sow's parity among 3 treatments: 1) CONTROL group, no oral supplementation to piglets; 2) EN group, light piglets (LP: birth BW ≤ 1.35 kg) received 2 doses of 1 mL Lianol Colostro; 3) COLO group, LP received 2 doses of 5 mL ColoBoost. Treatments were administered within 4 h after birth and repeated 8 h after the first dose. Piglets were weighed at d 0, 1, 10, and 21 after birth. Piglet rectal temperature was recorded shortly after birth and at 24 h. Cross-fostering was performed 24 h after birth. Blood samples were obtained from 39 LP at d 5 and 21 to determine IGF-I and IgG levels. Total mortality and LP mortality rate (percentage of LP in the litter that died) were recorded. At d 1, the EN group had a lower total mortality rate (2.1 vs. 7.1 ± 1.4%, = 0.036) and LP mortality rate (4.5 vs. 11.1 ± 2.8%, = 0.047) than the CONTROL group. At d 1, the COLO group tended to have a lower LP mortality rate than the CONTROL group (8.4 vs. 11.1 ± 3.0%, = 0.058). After cross-fostering, the COLO group had a lower LP mortality rate at d 21 than the CONTROL group (6.3 vs. 18.3 ± 2.8%, = 0.043). The total mortality rate and piglet body weight did not differ among groups at d 21. Piglets in the COLO group had a higher IgG level at d 5 than those in the EN group (24.9 vs. 16.3 ± 2.15 mg/mL, = 0.034) and tended to be higher than those in the CONTROL group (24.9 vs. 17.7 ± 2.35 mg/mL, = 0.072). Piglets in the EN group had a higher serum IGF-I concentration than those in the CONTROL group at d 21 (137.6 vs. 100.3 ± 11.15 ng/mL, = 0.030). The results suggested that 2 doses of oral supplementation within 12 h after birth might be effective in increasing small piglet survival and improving their IGF-I or IgG levels during lactation without compromising litter growth.

Emerging Therapeutic Options for Lowering of Lipoprotein(a): Implications for Prevention of Cardiovascular Disease.

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are an independent and causal risk factor for cardiovascular diseases including coronary artery disease, ischemic stroke, and calcific aortic valve stenosis. This review summarizes the rationale for Lp(a) lowering and surveys relevant clinical trial data using a variety of agents capable of lowering Lp(a). Contemporary guidelines and recommendations outline populations of patients who should be screened for elevated Lp(a) and who might benefit from Lp(a) lowering. Therapies including drugs and apheresis have been described that lower Lp(a) levels modestly (∼20%) to dramatically (∼80%). Existing therapies that lower Lp(a) also have beneficial effects on other aspects of the lipid profile, with the exception of Lp(a)-specific apheresis and an antisense oligonucleotide that targets the mRNA encoding apolipoprotein(a). No clinical trials conducted to date have managed to answer the key question of whether Lp(a) lowering confers a benefit in terms of ameliorating cardiovascular risk, although additional outcome trials of therapies that lower Lp(a) are ongoing. It is more likely, however, that Lp(a)-specific agents will provide the most appropriate approach for addressing this question.

Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials

Elevated lipoprotein(a) (Lp[a]) is a highly prevalent (around 20% of people) genetic risk factor for cardiovascular disease and calcific aortic valve stenosis, but no approved specific therapy exists to substantially lower Lp(a) concentrations. We aimed to assess the efficacy, safety, and tolerability of two unique antisense oligonucleotides designed to lower Lp(a) concentrations. We did two randomised, double-blind, placebo-controlled trials. In a phase 2 trial (done in 13 study centres in Canada, the Netherlands, Germany, Denmark, and the UK), we assessed the effect of IONIS-APO(a)Rx, an oligonucleotide targeting apolipoprotein(a). Participants with elevated Lp(a) concentrations (125-437 nmol/L in cohort A; ≥438 nmol/L in cohort B) were randomly assigned (in a 1:1 ratio in cohort A and in a 4:1 ratio in cohort B) with an interactive response system to escalating-dose subcutaneous IONIS-APO(a)Rx (100 mg, 200 mg, and then 300 mg, once a week for 4 weeks each) or injections of saline placebo, once a week, for 12 weeks. Primary endpoints were mean percentage change in fasting plasma Lp(a) concentration at day 85 or 99 in the per-protocol population (participants who received more than six doses of study drug) and safety and tolerability in the safety population. In a phase 1/2a first-in-man trial, we assessed the effect of IONIS-APO(a)-LRx, a ligand-conjugated antisense oligonucleotide designed to be highly and selectively taken up by hepatocytes, at the BioPharma Services phase 1 unit (Toronto, ON, Canada). Healthy volunteers (Lp[a] ≥75 nmol/L) were randomly assigned to receive a single dose of 10-120 mg IONIS-APO(a)LRx subcutaneously in an ascending-dose design or placebo (in a 3:1 ratio; single-ascending-dose phase), or multiple doses of 10 mg, 20 mg, or 40 mg IONIS-APO(a)LRx subcutaneously in an ascending-dose design or placebo (in an 8:2 ratio) at day 1, 3, 5, 8, 15, and 22 (multiple-ascending-dose phase). Primary endpoints were mean percentage change in fasting plasma Lp(a) concentration, safety, and tolerability at day 30 in the single-ascending-dose phase and day 36 in the multiple-ascending-dose phase in participants who were randomised and received at least one dose of study drug. In both trials, the randomised allocation sequence was generated by Ionis Biometrics or external vendor with a permuted-block randomisation method. Participants, investigators, sponsor personnel, and clinical research organisation staff who analysed the data were all masked to the treatment assignments. Both trials are registered with ClinicalTrials.gov, numbers NCT02160899 and NCT02414594. From June 25, 2014, to Nov 18, 2015, we enrolled 64 participants to the phase 2 trial (51 in cohort A and 13 in cohort B). 35 were randomly assigned to IONIS-APO(a)Rx and 29 to placebo. At day 85/99, participants assigned to IONIS-APO(a)Rx had mean Lp(a) reductions of 66·8% (SD 20·6) in cohort A and 71·6% (13·0) in cohort B (both p<0·0001 vs pooled placebo). From April 15, 2015, to Jan 11, 2016, we enrolled 58 healthy volunteers to the phase 1/2a trial of IONIS-APO(a)-LRx. Of 28 participants in the single-ascending-dose phase, three were randomly assigned to 10 mg, three to 20 mg, three to 40 mg, six to 80 mg, six to 120 mg, and seven to placebo. Of 30 participants in the multiple-ascending-dose phase, eight were randomly assigned to 10 mg, eight to 20 mg, eight to 40 mg, and six to placebo. Significant dose-dependent reductions in mean Lp(a) concentrations were noted in all single-dose IONIS-APO(a)-LRx groups at day 30. In the multidose groups, IONIS-APO(a)-LRx resulted in mean reductions in Lp(a) of 66% (SD 21·8) in the 10 mg group, 80% (SD 13·7%) in the 20 mg group, and 92% (6·5) in the 40 mg group (p=0·0007 for all vs placebo) at day 36. Both antisense oligonucleotides were safe. There were two serious adverse events (myocardial infarctions) in the IONIS-APO(a)Rx phase 2 trial, one in the IONIS-APO(a)Rx and one in the placebo group, but neither were thought to be treatment related. 12% of injections with IONIS-APO(a)Rx were associated with injection-site reactions. IONIS-APO(a)-LRx was associated with no injection-site reactions. IONIS-APO(a)-LRx is a novel, tolerable, potent therapy to reduce Lp(a) concentrations. IONIS-APO(a)-LRx might mitigate Lp(a)-mediated cardiovascular risk and is being developed for patients with elevated Lp(a) concentrations with existing cardiovascular disease or calcific aortic valve stenosis. Ionis Pharmaceuticals.

Serum lipoprotein(a) level as long-term predictor of cardiovascular mortality in a large sample of subjects in primary cardiovascular prevention: data from the Brisighella Heart Study

BackgroundHigh lipoprotein(a) [Lp(a)] levels have been re-evaluated as an independent risk factor for atherosclerotic vascular diseases. MethodsWe assessed whether serum Lp(a) levels can significantly influence long-term survival in subjects with an equal general cardiovascular (CV) risk profile.We prospectively evaluated a sample of 1215 adult subjects from the Brisighella Heart Study cohort (M: 608; F: 607; aged 40–69) who had no cardiovascular disease at enrolment. According to the CUORE project risk-charts (Italian-specific risk-charts), individuals were stratified into a low—(n=865), an intermediate—(n=275) and a high—(n=75) cardiovascular risk groups. Kaplan–Meier 25-year survival analysis was carried out examining apart each class of risk and the log-rank statistic was used to estimate, when statistically possible, the survival time of the subjects stratified into quartiles of Lp(a). ResultsSubjects at high and intermediate CV risk aged 56–69years (regardless of gender) and women aged 40–55years with a low CV risk profile who had lower Lp(a) levels showed a significant benefit on CV mortality (P<0.05 always) and, indicatively, on the estimated survival time (even P<0.05). The ROC curves constructing for each CV risk group using Lp(a) as test-variable and death as state-variable identified serum Lp(a) as an independent long-term CV mortality prognosticator for subjects at high CV risk (AUC=0.63, 95%CI [0.50–0.76], P=0.049) and women with an intermediate CV risk profile (AUC=0.7, 95%CI [0.52–0.79], P=0.034). ConclusionsIn the light of our finding and at the best of the previous knowledge, dosing Lp(a) is confirmed as important in subjects at high or medium risk (even if in primary prevention for CV diseases), especially in women.

Ischemic stroke in a young adult with extremely elevated lipoprotein(a): A case report and review of literature

Lipoprotein(a) [Lp(a)] is an apolipoprotein(a) molecule bound to 1 apolipoprotein B-100. Elevated levels of Lp(a) are thought to be an independent risk factor for atherosclerosis and to promote thrombosis through incompletely understood mechanisms. We report a 34-year-old man with an ischemic stroke in the setting of an extremely high Lp(a) level—212 mg/dL. He developed severe carotid artery stenosis over a 6-year period and had thrombus formation post-carotid endarterectomy. To our knowledge, this case is unique because the Lp(a) is the highest reported level in a patient without renal disease. Moreover, this is the first reported case of the youngest individual with a stroke presumably related to development of carotid plaque over a 6-year period. The thrombotic complication after endarterectomy may have been related to the prothrombotic properties of Lp(a). Of note, the Lp(a) level did not respond to atorvastatin but did decrease 15% after aspirin 325 mg was added although his Lp(a) levels were variable, and it is not clear that this was cause and effect. This case highlights the need to better understand the relation between Lp(a) and vascular disease and the need to screen family members for elevated Lp(a). We also review treatment options to lower Lp(a) and ongoing clinical trials of newer lipid-lowering drugs that can also lower Lp(a).

Abstract 235: Prevalence of Lipoprotein(a) Measurements and Extent of Lipoprotein(a) Elevations in 2,266 Patients with Aortic Stenosis: Results from an Academic Echocardiography Laboratory Practice Setting

Background: The LPA gene causes elevated lipoprotein(a) (Lp(a)) levels and causally mediates calcific aortic valve stenosis (AS). Elevated Lp(a) and its associated oxidized phospholipids (OxPL-apoB) predict the progression of pre-existing AS and need for aortic valve replacement and are targets of therapy. Methods: We determined the prevalence and the extent of Lp(a) elevation in patients with AS diagnosed by echocardiography performed at the University of California San Diego between 2010-2015. Severity of AS was classified as critical, severe, moderate, mild, or trace. Lp(a) levels were organized as Lp(a) &lt;30 mg/dL, 30-50 mg/dL, 50-100 mg/dL and &gt;100 mg/dL. Results: 2,266 patients with AS were found, with 130 critical, 333 severe, 477 moderate, 1318 mild, and 8 cases of trace AS. Mean age was 75.0 and range 18-106 years. 51% of patients were male. Prevalence of any Lp(a) measurement was 159/2,266 patients (7.02%). The number (%) of patients with an Lp(a) level was: 1) critical (n=4, 3.1%), 2) severe (n=28, 8.4%), 3) moderate (n=56, 11.7%), 4) mild (n=71, 5.4%), and 5) trace (n=0). The extent of Lp(a) elevation within each AS category is in Table 1: 55/159 (34%), 35/159 (22%) and 19/159 (12%) of patients had Lp(a) &gt;30 mg/dL, &gt;50 mg/dL and &gt;100 mg/dL, respectively. Conclusion: Lp(a) was measured in only 7.0% of patients with AS in an academic setting. Given the ongoing development of therapies to lower Lp(a) in patients with AS, educational efforts are needed to raise awareness of Lp(a) as a causal risk factor for AS.

Data on the lipoprotein (a), coronary atherosclerotic burden and vulnerable plaque phenotype in angiographic obstructive coronary artery disease.

Lipoprotein Lp(a) represents an independent risk factor for coronary artery disease (CAD). However, its association with CAD burden and lipid rich plaques prone to rupture in patients with acute coronary syndrome (ACS) still remains unknown. These data aim to investigate the association among serum Lipoprotein(a) (Lpa) levels, coronary atherosclerotic burden and features of culprit plaque in patients with ACS and obstructive CAD. For his reason, a total of 500 ACS patients were enrolled for the angiographic cohort and 51 ACS patients were enrolled for the optical coherence tomography (OCT) cohort. Angiographic CAD severity was assessed by Sullivan score and by Bogaty score including stenosis score and extent index, whereas OCT plaque features were evaluated at the site of the minimal lumen area and along the culprit segment. In the angiographic cohort, Lp(a) was a weak independent predictor of Sullivan score (p<0.0001), stenosis score (p<0.0001) and extent index (p<0.0001). In the OCT cohort, patients with higher Lp(a) levels (>30 md/dl) compared to patients with lower Lp(a) levels (<30 md/dl) exhibited a higher prevalence of lipidic plaque at the site of the culprit stenosis (P=0.02), a wider lipid arc (p=0.003) and a higher prevalence of thin-cap fibroatheroma (p=0.004)

Population and assay thresholds for the predictive value of lipoprotein (a) for coronary artery disease: the EPIC-Norfolk Prospective Population Study

Variable agreement exists between different lipoprotein (a) [Lp(a)] measurement methods, but their clinical relevance remains unclear. The predictive value of Lp(a) measured by two different assays [Randox and University of California, San Diego (UCSD)] was determined in 623 coronary artery disease (CAD) cases and 948 controls in a case-control study within the EPIC-Norfolk Prospective Population Study. Participants were divided into sex-specific quintiles, and by Lp(a) <50 versus ∼50 mg/dl, which represents the 80th percentile in northern European subjects. Randox and UCSD Lp(a) levels were strongly correlated; Spearman's correlation coefficients for men, women, and sexes combined were 0.905, 0.915, and 0.909, respectively (P< 0.001 for each). The >80th percentile cutoff values, however, were 36 mg/dl and 24 mg/dl for the Randox and UCSD assays, respectively. Despite this, Lp(a) levels were significantly associated with CAD risk, with odds ratios of 2.18 (1.58-3.01) and 2.35 (1.70-3.26) for people in the top versus bottom Lp(a) quintile for the Randox and UCSD assays, respectively. This study demonstrates that CAD risk is present at lower Lp(a) levels than the currently suggested optimal Lp(a) level of <50 mg/dl. Appropriate thresholds may need to be population and assay specific until Lp(a) assays are standardized and Lp(a) thresholds are evaluated broadly across all populations at risk for CVD and aortic stenosis.

DEFINING THE MECHANISM OF LP(A) LOWERING BY ALIROCUMAB IN TRANSGENIC MOUSE MODELS

Lp(a) consists of apo(a) covalently bound to apoB of LDL and is a causal, genetic risk factor for CVD and aortic stenosis. PCSK9 monoclonal antibodies, such as alirocumab and evolocumab, lower Lp(a) in humans by 9-38%, but the mechanisms are not well defined. We utilized transgenic apo(a)/Lp(a)

POTENT ANTISENSE OLIGONUCLEOTIDES TO APO(A) NORMALIZE PLASMA LP(A) LEVELS IN THE MAJORITY OF PEOPLE WITH ELEVATED LP(A): RESULTS OF ISIS-APO(A)RX PHASE 2 AND ISIS-APO(A)-LRX PHASE 1 TRIALS

Elevated Lp(a) levels are causal, independent predictors of CVD and aortic stenosis (AS). Specific therapies to potently lower Lp(a) are lacking. We assessed the safety and efficacy of ISIS-APO(a)Rx in patients with elevated Lp(a) and of ISIS-APO(a)-LRx, an optimized antisense oligonucleotide (ASO)

Lipoprotein(a) levels predict adverse vascular events after acute myocardial infarction.

Lipoprotein(a) [Lp(a)], which is genetically determined, has been reported as an independent risk factor for atherosclerotic vascular disease. However, the prognostic value of Lp(a) for secondary vascular events in patients after coronary artery disease has not been fully elucidated. This 3-year observational study included a total of 176 patients with ST-elevated myocardial infarction (STEMI), whose Lp(a) levels were measured within 24h after primary percutaneous coronary intervention. We divided enrolled patients into two groups according to Lp(a) level and investigated the association between Lp(a) and the incidence of major adverse cardiac and cerebrovascular events (MACCE). A Kaplan-Meier analysis demonstrated that patients with higher Lp(a) levels had a higher incidence of MACCE than those with lower Lp(a) levels (log-rank P=0.034). A multivariate Cox regression analysis revealed that Lp(a) levels were independently correlated with the occurrence of MACCE after adjusting for other classical risk factors of atherosclerotic vascular diseases (hazard ratio 1.030, 95% confidence interval: 1.011-1.048, P=0.002). In receiver-operating curve analysis, the cutoff value to maximize the predictive power of Lp(a) was 19.0mg/dl (area under the curve=0.674, sensitivity 69.2%, specificity 62.0%). Evaluation of Lp(a) in addition to the established coronary risk factors improved their predictive value for the occurrence of MACCE. In conclusion, Lp(a) levels at admission independently predict secondary vascular events in patients with STEMI. Lp(a) might provide useful information for the development of secondary prevention strategies in patients with myocardial infarction.