Longitudinal changes and borderline reclassification of Lipoprotein(a) compared with conventional lipids in over 230,000 adults.

We measured oxidized phospholipids (OxPL), lipoprotein (a) [Lp(a)], and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) pre- and postapheresis in 18 patients with familial hypercholesterolemia (FH) and with low(∼10 mg/dl; range 10-11 mg/dl), intermediate (∼50 mg/dl; range 30-61 mg/dl), or high (>100 mg/dl; range 78-128 mg/dl) Lp(a) levels. By using enzymatic and immunoassays, the content of OxPL and Lp-PLA(2) mass and activity were quantitated in lipoprotein density fractions plated in microtiter wells, as well as directly on apoB-100, Lp(a), and apoA-I immunocaptured within each fraction (i.e., OxPL/apoB and Lp-PLA(2)/apoB). In whole fractions, OxPL was primarily detected in the Lp(a)-containing fractions, whereas Lp-PLA(2) was primarily detected in the small, dense LDL and light Lp(a) range. In lipoprotein capture assays, OxPL/apoB and OxPL/apo(a) increased proportionally with increasing Lp(a) levels. Lp-PLA(2)/apoB and Lp-PLA(2)/apoA-I levels were highest in the low Lp(a) group but decreased proportionally with increasing Lp(a) levels. Lp-PLA(2)/apo(a) was lowest in patients with low Lp(a) levels and increased proportionally with increasing Lp(a) levels. Apheresis significantly reduced levels of OxPL and Lp-PLA(2) on apoB and Lp(a) (50-75%), particularly in patients with intermediate and high Lp(a) levels. In contrast, apheresis increased Lp-PLA(2)-specific activity (activity/mass ratio) in buoyant LDL fractions. The impact of apheresis on Lp(a), OxPL, and Lp-PLA(2) provides insights into its therapeutic benefits beyond lowering apoB-containing lipoproteins.

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

The aim of this study was to assess the independent contributions of plasma levels of lipoprotein(a) (Lp(a)), Lp(a) cholesterol, and of apo(a) isoform size to prospective coronary heart disease (CHD) risk. Plasma Lp(a) and Lp(a) cholesterol levels, and apo(a) isoform size were measured at examination cycle 5 in subjects participating in the Framingham Offspring Study who were free of CHD. After a mean follow-up of 12.3 years, 98 men and 47 women developed new CHD events. In multivariate analysis, the hazard ratio of CHD was approximately two-fold greater in men in the upper tertile of plasma Lp(a) levels, relative to those in the bottom tertile (P < 0.002). The apo(a) isoform size contributed only modestly to the association between Lp(a) and CHD and was not an independent predictor of CHD. In multivariate analysis, Lp(a) cholesterol was not significantly associated with CHD risk in men. In women, no association between Lp(a) and CHD risk was observed. Elevated plasma Lp(a) levels are a significant and independent predictor of CHD risk in men. The assessment of apo(a) isoform size in this cohort does not add significant information about CHD risk. In addition, the cholesterol content in Lp(a) is not a significant predictor of CHD risk.

Background/Introduction In the context of novel risk factors in cardiovascular disease (CVD) spectrum, lipoprotein (a) (Lp(a)) is a highly discussed biomarker with promising evidence. Purpose The association between Lp(a) and 10-year first fatal/non fatal CVD event in free of CVD males and females was evaluated. Methods A longitudinal prospective study was conducted during 2001–2012, studying 1,514 males and 1,528 females (aged &gt;18 years old). Follow-up assessment of CVD (2011–2012) was achieved in n=2,020 participants (n=317 cases). Of them, baseline Lp(a) was measured in n=1,890 participants. The recommended threshold of 50mg/dL was used to define abnormal Lp(a) status (≥50mg/dL). Effect-size of Lp(a) on CVD was evaluated through Cox-regression analysis while its discrimination ability through C-statistics. Results Ten-year CVD event rate was 14% and 24% in participants with Lp(a)&lt;50 mg/dL and Lp(a)≥50 mg/dL, respectively (p=0.05). In multivariate analysis those with Lp(a)≥50 mg/dL had two times higher risk to develop CVD compared with participants with normal Lp(a) (Hazard Ratio (HR)=2.18, 95% Confidence Interval (95% CI) 1.11, 4.28, p=0.04). Sex-based stratified analysis revealed that the independent Lp(a)-effect on CVD was retained only in males (HR=2.00, 95% CI 1.19, 2.56, p=0.05); while in females significance was lost when adjusting for low and high density lipoprotein (LDL-C, HDL-C), triglycerides and statins use (p for sex interaction=0.01). Sensitivity analyses revealed that Lp(a) significantly increased CVD risk only in case of abnormal HDL-C, apolipoprotein A1 and triglycerides; interestingly, the interaction between these lipid markers, sex and Lp(a) was significant (p for interaction=0.001) implying that this observation could be sex-mediated. C-indexes and correct classification rates of a standard model with three different levels of adjustment (i.e. Lp(a) or conventional lipid markers or combined lipid markers) were evaluated per sex. In females, the highest total correct classification rate was higher in model adjusted for conventional lipid markers (89.6%) with the rate corresponding to CVD cases being more than twice as high in Lp(a)-adjusted model (19.6% vs. 8.5%) and lower than in fully adjusted model (15.7%). A similar ranking was observed in case of C-indexes (0.831 vs. 0.820 vs. 0.829). Males presented the best total correct classification rate in fully adjusted model (96.5%). Case-related correct classification rate was about 3 times higher in Lp(a)-adjusted model compared with the respective rate in females (24.7% vs. 8.5%). C-index after Lp(a) adjustment in the model with conventional lipid markers increased by 0.01 (i.e. 0.772 vs. 0.784). Conclusion While ever increasing efforts have sought to elucidate Lp(a) as a therapeutic target or risk-prediction biomarker in CVD prevention clinical recommendations remain to be guided with appropriate conclusive evidence, mostly from a sex-centered standpoint. Acknowledgement/Funding The ATTICA study is supported by research grants from the Hellenic Cardiology Society [HCS2002] and the Hellenic Atherosclerosis Society [HAS2003].

Background: Cohort studies and clinical trials have shown a greater prevalence of diabetes among subjects with lower levels of lipoprotein(a) [Lp(a)]. Some healthy cohort studies have shown a greater incidence of new onset diabetes (NOD) among those with lower Lp(a). It is unknown whether the risk of NOD associates with Lp(a) levels in patients (pts) with established cardiovascular disease or whether pharmacologic reduction of Lp(a) with PCSK9 inhibitors modulates this risk. Objective: Using data from the ODYSSEY OUTCOMES trial that compared the PCSK9 inhibitor alirocumab (ALI) with placebo (PBO) in pts with recent acute coronary syndrome, we examined whether NOD was related to baseline Lp(a) level and whether any such relationship was modified by ALI treatment. Methods and Results: Lp(a) was measured with a mass assay in 13,480 trial pts without diabetes at baseline; median (IQR) baseline Lp(a) was 21.9 mg/dL (6.9-61.1); median follow-up was 2.7 years. Intensive statin therapy was utilized in 89%. In the PBO group, NOD was greatest in Quartile 1 and least in Quartile 4 of baseline Lp(a) ( Figure , 4.6 vs 3.1 cases per 100 pt-years, P trend 0.0003). ALI lowered Lp(a) by a median of 23% from baseline. Absolute median reduction in Lp(a) with ALI ranged from nil in baseline Lp(a) Quartile 1 to 15 mg/dL in Quartile 4. Treatment HR (ALI/PBO) for NOD was neutral overall (0.95, 95% CI 0.85-1.05) but varied across baseline Lp(a) quartiles from 0.79 (0.64-0.96) in Quartile 1 to 1.09 (0.87-1.38) in Quartile 4 ( Figure , P trend =0.025). Conclusion: In pts with recent acute coronary syndrome, there is greater NOD among those with lower baseline Lp(a) levels. ALI has an overall neutral effect on NOD: In pts with low baseline Lp(a), ALI has minimal effect on Lp(a) levels and tends to reduce NOD. In pts with high baseline Lp(a), ALI reduces Lp(a) levels with a non-significant excess of NOD. The findings may have implications for emerging therapies that reduce Lp(a) more substantially than PCSK9 inhibitors.

Background: Lipoprotein (a) (Lp(a)) has been implicated in atherothrombogenesis and prior studies have suggested its pathogenic role in the development of intracranial atherosclerosis (ICAS). Objective: We sought to determine the association between baseline Lp(a) levels and risk of vascular events during follow-up in patients randomized to the medical arm of the SAMMPRIS trial. Methods: Baseline Lp(a) data was available for 226 of 227 patients randomized to the medical arm in SAMMPRIS. High Lp(a) was defined as &gt; 65 mg/dL in Blacks and &gt; 35 mg/dL in Whites and Others. The primary outcome was any ischemic stroke and the secondary outcome was a composite of vascular events (ischemic stroke, MI and vascular death). Kaplan-Meier curves for the time to the outcomes were compared between patients with high and low Lp(a) using the log-rank test. Using Lp(a) as a continuous variable, Cox proportional hazards model was used to determine the association between Lp(a) and time to outcomes of interest. Results: Overall, 17/92 (18.5%) patients with high Lp(a) levels had an ischemic stroke during follow-up versus 24/134 (17.9%) with normal Lp(a) levels, with no difference between the Kaplan-Meier curves of the groups (p=0.94). In a Cox proportional hazards model relating Lp(a) to time to ischemic stroke, Lp(a) was not statistically significant (p = 0.82). Similarly, 23/92 (25%) patients with high Lp(a) levels had a vascular event during follow-up versus 29/134 (21.6%) with normal Lp(a) levels, with no difference between the Kaplan-Meier curves (p=0.58). In a Cox proportional hazards model relating Lp(a) to time to ischemic stroke, MI, or vascular death, Lp(a) was not statistically significant (p = 0.46). Conclusion: Patients with high Lp(a) levels in the SAMMPRIS trial did not have an increased risk of ischemic strokes or vascular events during follow-up. Although prior studies have suggested a pathogenic contribution of high Lp(a) to the development of ICAS, our results do not find an association between high Lp(a) and increased risk of vascular events.

Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for coronary heart disease (CHD) events. However, few data exist on the clinical importance of Lp(a) lowering for CHD prevention. Hormone therapy with estrogen has been found to lower Lp(a) levels in women. To determine the relationships among treatment with estrogen and progestin, serum Lp(a) levels, and subsequent CHD events in postmenopausal women. The Heart and Estrogen/progestin Replacement Study (HERS), a randomized, blinded, placebo-controlled secondary prevention trial conducted from January 1993 through July 1998 with a mean follow-up of 4.1 years at 20 centers. A total of 2763 postmenopausal women younger than 80 years with coronary artery disease and an intact uterus. Mean age was 66.7 years. Participants were randomly assigned to receive either conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, in 1 tablet daily (n = 1380), or identical placebo (n = 1383). Lipoprotein(a) levels and CHD events (nonfatal myocardial infarction and CHD death). Increased baseline Lp(a) levels were associated with subsequent CHD events among women in the placebo arm. After multivariate adjustment, women in the second, third, and fourth quartiles of baseline Lp(a) level had relative hazards (RHs) (compared with the first quartile) of 1.01 (95% confidence interval [CI], 0.64-1.59), 1.31 (95% CI, 0.85-2.04), and 1.54 (95% CI, 0.99-2.39), respectively, compared with women in the lowest quartile (P for trend = .03). Treatment with estrogen and progestin reduced mean (SD) Lp(a) levels significantly (-5.8 [15] mg/dL) (-0.20 [0.53] micromol/L) compared with placebo (0.3 [17] mg/dL) (0.01 [0.60] micromol/L) (P<.001). In a randomized subgroup comparison, women with low baseline Lp(a) levels had less benefit from estrogen and progestin than women with high Lp(a) levels; the RH for women assigned to estrogen and progestin compared with placebo were 1.49 (95% CI, 0.97-2.26) in the lowest quartile and 1.05 (95% CI, 0.67-1.65), 0.78 (0.52-1.18), and 0.85 (0.58-1.25) in the second, third, and fourth quartiles, respectively (P for interaction trend = .03). Our data suggest that Lp(a) is an independent risk factor for recurrent CHD in postmenopausal women and that treatment with estrogen and progestin lowers Lp(a) levels. Estrogen and progestin therapy appears to have a more favorable effect (relative to placebo) in women with high initial Lp(a) levels than in women with low levels. This apparent interaction needs confirmation in other trials.

ContextLipoprotein(a) [Lp(a)] has been identified as an independent risk factor for coronary heart disease (CHD) events. However, few data exist on the clinical importance of Lp(a) lowering for CHD prevention. Hormone therapy with estrogen has been found to lower Lp(a) levels in women.ObjectiveTo determine the relationships among treatment with estrogen and progestin, serum Lp(a) levels, and subsequent CHD events in postmenopausal women.Design and SettingThe Heart and Estrogen/progestin Replacement Study (HERS), a randomized, blinded, placebo-controlled secondary prevention trial conducted from January 1993 through July 1998 with a mean follow-up of 4.1 years at 20 centers.ParticipantsA total of 2763 postmenopausal women younger than 80 years with coronary artery disease and an intact uterus. Mean age was 66.7 years.InterventionParticipants were randomly assigned to receive either conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, in 1 tablet daily (n = 1380), or identical placebo (n = 1383).Main Outcome MeasuresLipoprotein(a) levels and CHD events (nonfatal myocardial infarction and CHD death).ResultsIncreased baseline Lp(a) levels were associated with subsequent CHD events among women in the placebo arm. After multivariate adjustment, women in the second, third, and fourth quartiles of baseline Lp(a) level had relative hazards (RHs) (compared with the first quartile) of 1.01 (95% confidence interval [CI], 0.64-1.59), 1.31 (95% CI, 0.85-2.04), and 1.54 (95% CI, 0.99-2.39), respectively, compared with women in the lowest quartile (P for trend = .03). Treatment with estrogen and progestin reduced mean (SD) Lp(a) levels significantly (–5.8 [15] mg/dL) (−0.20 [0.53] µmol/L)compared with placebo (0.3 [17] mg/dL) (0.01 [0.60] µmol/L) (P<.001). In a randomized subgroup comparison, women with low baseline Lp(a) levels had less benefit from estrogen and progestin than women with high Lp(a) levels; the RH for women assigned to estrogen and progestin compared with placebo were 1.49 (95% CI, 0.97-2.26) in the lowest quartile and 1.05 (95% CI, 0.67-1.65), 0.78 (0.52-1.18), and 0.85 (0.58-1.25) in the second, third, and fourth quartiles, respectively (P for interaction trend = .03).ConclusionsOur data suggest that Lp(a) is an independent risk factor for recurrent CHD in postmenopausal women and that treatment with estrogen and progestin lowers Lp(a) levels. Estrogen and progestin therapy appears to have a more favorable effect (relative to placebo) in women with high initial Lp(a) levels than in women with low levels. This apparent interaction needs confirmation in other trials.

The proprotein convertase subtilisin/kexin Type 9 inhibitor, evolocumab, promoted plaque stabilization on serial imaging in patients following an acute coronary syndrome. The impact of evolocumab in patients with varying lipoprotein(a) [Lp(a)] levels is unknown. Serial optical coherence tomography imaging was performed to evaluate changes in plaque composition in response to treatment with evolocumab 420 mg or placebo for 50 weeks. The current post hoc analysis compared demographics, biochemistry, and plaque imaging changes in those with baseline Lp(a) levels <125 (n = 71) and ≥125 nmol/L (n = 46). Among those with high Lp(a) levels, evolocumab treatment produced lower levels of LDL cholesterol (LDL-C) (21.7 ± 10.3 vs. 94.5 ± 22.9 mg/dL; P < 0.001) and Lp(a) [156.0 (136.0, 187.0) vs. 204.0 (170.5, 290.5) nmol/L; P = 0.007], compared with placebo. Changes in minimum fibrous cap thickness (FCT) (+51.6 ± 40.9 vs. +12.4 ± 23.9 μm; P < 0.001) and lipid arc (-60.9 ± 56.5° vs. -9.1 ± 70.8°; P = 0.008) were greater in the high Lp(a) group with evolocumab compared with placebo. Among patients with low Lp(a) levels, evolocumab produced lower levels of LDL-C (23.3 ± 34.9 vs. 82.9 ± 46.5 mg/dL; P < 0.001) and Lp(a) [11.5 (5.8, 23.8) vs. 25.0 (13.5, 41.0) nmol/L; P = 0.01] compared with placebo, but no differences were observed between groups in changes in minimum FCT (+45.9 ± 37.8 vs. +34.7 ± 36.0 μm; P = 0.21) and lipid arc (-59.9 ± 50.1° vs. -44.5 ± 46.1°; P = 0.18). Baseline Lp(a) levels significantly interacted with the impact of evolocumab on changes in minimum FCT (interaction P = 0.04). The ability of evolocumab to more effectively promote plaque stabilization, compared with statin monotherapy, appears more pronounced in patients with higher Lp(a) levels, suggesting that Lp(a) may help identify those who benefit most from intensive lipid-lowering therapy. ClinicalTrials.gov: NCT03570697.

Plasma lipoprotein(a) [Lp(a)] concentrations and cardiovascular events in the elderly: evidence from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)

Lipoprotein(a) [Lp(a)] has enhanced atherothrombotic properties. The ability of Lp(a) levels to predict adverse cardiovascular outcomes in patients undergoing coronary angiography has not been examined. The relationship between serum Lp(a) levels and both the extent of angiographic disease and 3-year incidence of major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, and coronary revascularization) was investigated in 2,769 patients who underwent coronary angiography [median Lp(a) 16.4 mg/dl, elevated levels (≥30 mg/dl) in 38%]. An elevated Lp(a) was associated with a 2.3-fold [95% confidence interval (CI), 1.7-3.2, P < 0.001] greater likelihood of having a significant angiographic stenosis and 1.5-fold (95 CI, 1.3-1.7, P < 0.001) greater chance of three-vessel disease. Lp(a)≥30 mg/dl was associated with a greater rate of MACE (41.8 vs. 35.8%, P = 0.005), primarily due to a greater need for coronary revascularization (30.9 vs. 26.0%, P = 0.02). A relationship between Lp(a) levels and cardiovascular outcome was observed in patients with an LDL cholesterol (LDL-C) ≥70-100 mg/dl (P = 0.049) and >100 mg/dl (P = 0.02), but not <70 mg/dl (P = 0.77). Polymorphisms of Lp(a) were also associated with both plasma Lp(a) levels and coronary stenosis, but not a greater rate of MACE. Lp(a) levels correlate with the extent of obstructive disease and predict the need for coronary revascularization in subjects with suboptimal LDL-C control. This supports the need to intensify lipid management in patients with elevated Lp(a) levels.

Introduction: Serum lipoprotein(a) [Lp(a)] is genetically determined and has been proposed to be associated with coronary artery lesion severity and clinical outcomes in coronary artery disease (CAD). But some researches suggested heterogeneous effects and marked variations of Lp(a) level between ethnic groups. The aim of this study was to investigate the impact of baseline Lp(a) on five-year clinical outcomes in Chinese population who underwent coronary artery bypass grafting (CABG). Methods: We performed a post-hoc analysis of the DACAB trial (NCT02201771), in which patients aged 18 to 80 years, male or female, underwent primary, isolated and elective CABG, were randomly assigned to receive different antiplatelet treatments. Serum Lp(a) was obtained and analyzed in 270/272 patients of one single center. The primary outcome was major adverse cardiovascular events (MACE). MACE-5 included all-cause death, myocardial infarction, stroke, repeated revascularization and rehospitalization for unstable angina, and MACE-3 included cardiovascular death, myocardial infarction, and stroke. The mean follow-up reached 59.4±9.4 months. Results: The baseline characteristics were generally comparable. High Lp(a) level was identified in 71 (26.3%) (cut-off ≥30mg/dL) and 33 (12.2%) (cut-off ≥50mg/dL) patients, respectively. During 5-year follow-up, MACE-5 reported in high and low Lp(a) group were 34.2% vs 28.8% when the cut-off value was 30mg/dL (hazard ratio [HR], 1.11; 95% CI, 0.69-1.78, p=0.66). While the cut-off value was 50mg/dL, MACE-5 reported in high and low Lp(a) group were 39.4% vs 28.9% (HR, 1.32; 95% CI, 0.73-2.38, p=0.36). Similar results were observed in MACE-3 (Cut-off value 30mg/dL: 24.2% vs 21.9%, HR 1.08, p=0.78; Cut-off value 50mg/dL: 27.3% vs 21.8%, HR 1.24, p=0.56). No statistical significant difference was achieved between the two groups. Conclusions: In this single center post-hoc analysis, baseline Lp(a) level ≥30mg/dL or ≥50mg/dL had no statistical significant association with 5-year MACE in post-CABG Chinese population. But higher baseline Lp(a) levels seem to be associated with more MACE in longer follow-up. Larger sample size from multicenter are needed to confirm our findings.

Increased risk of coronary artery calcification progression in subjects with high baseline Lp(a) levels: The Kangbuk Samsung Health Study

Residual lipoprotein(a)-associated risk in patients with stroke or transient ischemic attack.

BackgroundRecent studies suggest an association between Lipoprotein(a) [Lp(a)] and the development of diabetes mellitus. We analyzed the association between baseline Lp(a) levels and diabetes development after 4 years of follow-up, in a population of apparently healthy Korean subjects.MethodsA total of 2,536 non-diabetic participants (mean age: 41 years, men: 92%) of a health checkup program were included in the study. Diabetes development was defined by fasting blood glucose ≥126 mg/dL, HbA1c ≥6.5%, and self-reported treatment of diabetes. Homeostasis model assessment (HOMA) indices were used to assess insulin resistance (IR) and insulin secretion (IS). Presence of IR and impaired IS was defined by being in the highest quartile of HOMA-IR and in the lowest quartile HOMA-IS.ResultsAfter four years, 3.4% of the participants developed diabetes. The odds ratio (OR) of developing diabetes was lowest in the 4th quartile group of baseline Lp(a) (0.323 [95% CI 0.153–0.685])with the 1st quartile group as the reference. The subjects with both IR & impaired IS plus baseline Lp(a)<50 mg/dL showed the higher OR for diabetes development compared with those without IR and normal IS as the reference (67.277 [20.218–223.871], and those with IR plus Lp(a)<50 mg/dL showed higher OR for diabetes than in those with impaired IS and Lp(a)<50 mg/dL (3.811 [1.938–7.495] vs. 3.452 [1.620–7.353]).ConclusionsThe subjects with low baseline Lp(a) level showed higher risk for development of diabetes compared with high baseline Lp(a) level, and this was prominent in those with IR than in those with impaired IS.