Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease.

BACKGROUND: Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed. RESULTS: Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain. CONCLUSIONS: Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).

Lipoprotein(a) levels in children with suspected familial hypercholesterolaemia: a cross-sectional study.

AIMS: Familial hypercholesterolaemia (FH) predisposes children to the early initiation of atherosclerosis and is preferably diagnosed by DNA analysis. Yet, in many children with a clinical presentation of FH, no mutation is found. Adult data show that high levels of lipoprotein(a) [Lp(a)] may underlie a clinical presentation of FH, as the cholesterol content of Lp(a) is included in conventional LDL cholesterol measurements. As this is limited to adult data, Lp(a) levels in children with and without (clinical) FH were evaluated. METHODS AND RESULTS: Children were eligible if they visited the paediatric lipid clinic (1989-2020) and if Lp(a) measurement and DNA analysis were performed. In total, 2721 children (mean age: 10.3 years) were included and divided into four groups: 1931 children with definite FH (mutation detected), 290 unaffected siblings/normolipidaemic controls (mutation excluded), 108 children with probable FH (clinical presentation, mutation not detected), and 392 children with probable non-FH (no clinical presentation, mutation not excluded). In children with probable FH, 32% were found to have high Lp(a) [geometric mean (95% confidence interval) of 15.9 (12.3-20.6) mg/dL] compared with 10 and 10% [geometric means (95% confidence interval) of 11.5 (10.9-12.1) mg/dL and 9.8 (8.4-11.3) mg/dL] in children with definite FH (P = 0.017) and unaffected siblings (P = 0.002), respectively. CONCLUSION: Lp(a) was significantly higher and more frequently elevated in children with probable FH compared with children with definite FH and unaffected siblings, suggesting that high Lp(a) may underlie the clinical presentation of FH when no FH-causing mutation is found. Performing both DNA analysis and measuring Lp(a) in all children suspected of FH is recommended to assess possible LDL cholesterol overestimation related to increased Lp(a).

Concentration of Lp(a) (Lipoprotein[a]) in Aneurysm Sac Is Associated With Wall Enhancement of Unruptured Intracranial Aneurysm.

BACKGROUND AND PURPOSE: Atherosclerotic remodeling of the aneurysm wall, which could be detected as aneurysm wall enhancement (AWE) by magnetic resonance-vessel wall imaging, is a part of degenerative change of unruptured intracranial aneurysms (UIAs). The purpose of this study was to determine whether the luminal concentrations of atherosclerotic proteins in the aneurysm sac were associated with increased wall enhancement of UIAs in vessel wall imaging. METHODS: We performed a prospective study of subjects undergoing endovascular treatments for UIAs. All subjects underwent evaluation using 3T-magnetic resonance imaging, including pre/postcontrast vessel wall imaging of the UIAs. Blood samples were collected from the aneurysm sac and the parent artery during endovascular procedures. Presence/absence of AWE was correlated with the delta difference in concentration for each atherosclerotic protein between the lumen of UIA and in the parent artery. RESULTS: A total of consecutive 17 patients with 19 UIAs were enrolled. The delta difference of lipoprotein(a) was significantly higher in UIAs with AWE compared with those without AWE (-6.9±16.0 versus -45.4±44.9 µg/mL, P=0.03). CONCLUSIONS: Higher luminal concentrations of lipoprotein(a) in the aneurysm sac were significantly associated with increased wall enhancement of UIAs. A larger study is needed to confirm these findings.

Lipoprotein(a) and Cardiovascular Disease.

BACKGROUND: High lipoprotein(a) concentrations present in 10%-20% of the population have long been linked to increased risk of ischemic cardiovascular disease. It is unclear whether high concentrations represent an unmet medical need. Lipoprotein(a) is currently not a target for treatment to prevent cardiovascular disease. CONTENT: The present review summarizes evidence of causality for high lipoprotein(a) concentrations gained from large genetic epidemiologic studies and discusses measurements of lipoprotein(a) and future treatment options for high values found in an estimated >1 billion individuals worldwide. SUMMARY: Evidence from mechanistic, observational, and genetic studies support a causal role of lipoprotein(a) in the development of cardiovascular disease, including coronary heart disease and peripheral arterial disease, as well as aortic valve stenosis, and likely also ischemic stroke. Effect sizes are most pronounced for myocardial infarction, peripheral arterial disease, and aortic valve stenosis where high lipoprotein(a) concentrations predict 2- to 3-fold increases in risk. Lipoprotein(a) measurements should be performed using well-validated assays with traceability to a recognized calibrator to ensure common cut-offs for high concentrations and risk assessment. Randomized cardiovascular outcome trials are needed to provide final evidence of causality and to assess the potential clinical benefit of novel, potent lipoprotein(a) lowering therapies.

Residual Cardiovascular Risk at Low LDL: Remnants, Lipoprotein(a), and Inflammation.

BACKGROUND: Current guidelines target low-density lipoprotein cholesterol (LDL-C) concentrations to reduce atherosclerotic cardiovascular disease (ASCVD) risk, and yet clinical trials demonstrate persistent residual ASCVD risk despite aggressive LDL-C lowering. CONTENT: Non-LDL-C lipid parameters, most notably triglycerides, triglyceride-rich lipoproteins (TGRLs), and lipoprotein(a), and C-reactive protein as a measure of inflammation are increasingly recognized as associated with residual risk after LDL-C lowering. Eicosapentaenoic acid in statin-treated patients with high triglycerides reduced both triglycerides and ASCVD events. Reducing TGRLs is believed to have beneficial effects on inflammation and atherosclerosis. High lipoprotein(a) concentrations increase ASCVD risk even in individuals with LDL-C < 70 mg/dL. Although statins do not generally lower lipoprotein(a), proprotein convertase subtilisin/kexin type 9 inhibitors reduce lipoprotein(a) and cardiovascular outcomes, and newer approaches are in development. Persistent increases in C-reactive protein after intensive lipid therapy have been consistently associated with increased risk for ASCVD events. SUMMARY: We review the evidence that biochemical assays to measure TGRLs, lipoprotein(a), and C-reactive protein are associated with residual risk in patients treated to low concentrations of LDL-C. Growing evidence supports a causal role for TGRLs, lipoprotein(a), and inflammation in ASCVD; novel therapies that target TGRLs, lipoprotein(a), and inflammation are in development to reduce residual ASCVD risk.

Lipoprotein(a) in patients with hepatocellular carcinoma and portal vein thrombosis.

BACKGROUND: The mechanism for hypercoagulability in malignancy is not entirely understood. Although several studies report contrasting finding about the link between elevated plasma levels of the lipoprotein(a) [Lp(a)] and the possible recurrence of venous thromboembolism, we perform a study to evaluate the impact of the Lp(a) in the development of portal vein thromboembolism (PVT) in patients with HCC. METHODS: We compared 44 PVT patients with 50 healthy subjects and 50 HCC patients. RESULTS: The comparison between PVT patients and HCC showed in the former the mean value of serum lipoprotein levels was higher than 37.3 mg/dl (p = 0.000). The comparison between PVT versus healthy controls showed that in the former, mean value of serum lipoprotein levels was higher than 75 mg/dl (p = 0.000). The predictive value test of serum lipoprotein(a) on PVT was 0.72 and on HCC was 0.83. The odds ratio of lipoprotein(a) was 9.21 on PVT and 6.33 on HCC. CONCLUSION: Patients with PVT and HCC showed a statistical significant serum lipoprotein(a) level higher than the subjects with HCC and no PVT or the healthy subject. So we assume a role of lipoprotein(a) as predictor of venous thromboembolism in neoplastic patients.

Lipoprotein Lp(a) in lipoprotein spectrum indentified by Lipoprint LDL system.

OBJECTIVE: Identification of lipoprotein subfractions in lipoprotein profile by Lipoprint LDL system, where a lipoprotein(a), an independent risk factor for the development of cardiovascular disease, migrates with. The concentration of lipoprotein(a) in serum over 0.3 g/l increases the risk of athero-thrombosis and a brain stroke. The persons with increased levels of lipoprotein(a) and contemporarily increased cholesterol level in serum, are at increased risk of the inception of cardiovascular or cerebrovascular event even 3-times. PATIENTS AND METHODS: In a general group of subjects with increased serum concentration of lipoprotein(a) a lipoprotein profile analysis was performed. The general group of subjects was divided into two groups: subgroup with the lipoprotein(a) concentration in the range between 0.3-0.8 g/l and a subgroup with the lipoprotein(a) concentration over 0.8 g/l, to learn if the lipoprotein(a) particles of different serum concentration and different size do not migrate in different positions of the lipoprotein spectrum. For the analysis of serum lipoproteins an innovated electrophoresis method on polyacrylamide gel (PAG) - Lipoprint LDL system USA, was used. Lipids: a total cholesterol and triglycerides in serum were analysed by an enzymatic method CHOD PAP (Roche Diagnostics, FRG), lipoprotein(a) was analysed by an immuno-nephelometric method (Roche Diagnostics, FRG). RESULTS: In the Lipoprint LDL system using a polyacrylamide gel (PAG) for the lipoprotein separation, lipoprotein(a) migrates in the position IDL2-IDL3. In the band of IDL2 a high Lp(a) values can be identified, when the increment of IDL2 subfraction is over the value of 0.015 g/l, i.e. 15 mg/dl (reference range for IDL2) and when the increment of IDL3 subfraction is over the value of 25 mg/dl, i.e. 0.025 g/l (reference range for IDL3). CONCLUSIONS: A clear contribution of new method is: identification of the lipoprotein subpopulations where the lipoprotein(a) migrates with different migration position for the mild increased lipoprotein(a) concentration and high lipoprotein(a) concentration in serum was not confirmed.

[Abnormal semen liquefaction and seminal plasma lipoprotein (a)].

OBJECTIVE: To explore the effect of seminal plasma lipoprotein (a) in abnormal semen liquefaction and its clinical significance. METHODS: According to The WHO Laboratory Manual for the Examination and Processing of Human Semen, we conducted semen routine analyses of 101 patients with abnormal semen liquefaction and 26 normal healthy controls. We added chymotrypsin to the semen for 30 minutes of incubation at 37 degrees C. When there were filaments, we centrifuged the semen and obtained the upper seminal plasma to determine the level of lipoprotein (a). RESULTS: The level of lipoprotein (a) was significantly higher in the 101 patients ([526.2 +/- 243.5] mg/L) than in the 26 normal controls ([296.9 +/- 105.2] mg/L) (P < 0.01) . CONCLUSION: Lipoprotein (a) can inhibit fibrin dissolution, and delayed fibrin dissolution in semen liquefaction may be related to the increased level of seminal plasma lipoprotein (a). The seminal plasma lipoprotein (a) level should be taken into account in the clinical diagnosis of male infertility caused by abnormal semen liquefaction.

The development of lipoprotein apheresis in Saxony in the last years.

METHODS: Three hundred thirty-nine patients (230 men, 109 women) treated with lipoprotein apheresis in Saxony, Germany, in 2018 are described in terms of age, lipid pattern, risk factors, cardiovascular events, medication, and number of new admissions since 2014, and the data are compared with figures from 2010 to 2013. RESULTS: Patients were treated by 45.5 physicians in 16 lipoprotein apheresis centers. With about 10 patients per 100 000 inhabitants, the number of patients treated with lipoprotein apheresis in Saxony is twice as high as in Germany as a whole. The median treatment time was 3 years. Almost all patients had hypertension; type 2 diabetes mellitus was seen significantly more often in patients with low Lipoprotein(a). Cardiovascular events occurred in almost all patients before initiation of lipoprotein apheresis, under apheresis therapy the cardiovascular events rate was very low in this high-risk group. For some cardiovascular regions even no events could be observed. CONCLUSIONS: The importance of lipoprotein apheresis in Saxony had been increasing from 2010 to 2018.

[Case of cerebral venous thrombosis with a high plasma lipoprotein (a) level].

A 28-year-old man was admitted to our hospital because of severe headache and diplopia. Enhanced CT of the head revealed defects of contrast enhancement in the superior sagittal sinus and the right transverse sinus. Accordingly, he was diagnosed as suffering from cerebral venous thrombosis. The patient made a good recovery after receiving anticoagulant therapy. Investigations revealed a high plasma lipoprotein (a) [Lp (a)] level of 142 mg/ dl. We thought that his high Lp (a) level was associated with a thrombotic tendency. His mother also had an elevated plasma Lp (a) level of 45 mg/dl. Cerebral venous thrombosis of unknown etiology is not rare. In such patients, we should investigate the plasma Lp (a) level.

[Recent advances in the research on HDL subfraction].

High-density lipoprotein (HDL) is the smallest lipoprotein, with a density range of 1.063-1.210. HDL plays a crucial role in reverse cholesterol transport. Epidemiological studies have consistently shown that HDL-cholesterol (HDL-C) is inversely correlated with the incidence of coronary heart disease (CHD). HDL is composed of heterogeneous particles with different compositions and functions. For more precise prediction of CHD, researchers measure HDL subfractions which are separated by various methods based on their physicochemical properties. In this article, we briefly review the methods for measuring HDL subfractions and their clinical significance. We also address future perspectives in HDL subfraction measurements in the "Era of HDL therapy."

Lipoprotein(a) particle number assay without error from apolipoprotein(a) size isoforms.

BACKGROUND: Lipoprotein(a) [Lp(a)] is an important cardiovascular risk factor, but clinical immunoassays are flawed. Apolipoprotein(a) [apo(a)], the characteristic protein of Lp(a), contains a variable number of kringle repeats (size isoforms) that make accurate measurement of Lp(a) difficult. We developed a sandwich enzyme immunoassay that uses a murine monoclonal anti-apo(a) antibody for capture and a polyclonal anti-apolipoprotein B (apo B) for detection. Because Lp(a) contains one molecule each of apo(a) and apo B, the assay measures the number of Lp(a) particles [Lp(a)-P] in the circulation without bias due to apo(a) size isoforms. METHODS: After developing and choosing the best anti-apo(a) clone for Lp(a) capture, we identified suitable reagents and ELISA conditions, and validated assay performance (precision, linearity, limit of detection, interferences, and apo(a) size isoform bias). RESULTS: The Lp(a)-P assay was precise with within-run precision of 5.5% to 7.2% and total imprecision of 6.9% to 12.1%. The assay had a limit of detection of 13 nmol/l and was linear from 2 to 499 nmol/l. There was no interference from plasminogen or apolipoprotein B up to 80 and 200 mg/dl, respectively, and bias plot showed no bias related to apo(a) size (kringle 4 type 2 repeats). CONCLUSIONS: Lp(a)-P assay is sensitive, precise and linear over a wide analytical range and is a suitable alternative for laboratories concerned about inaccuracy due to apo(a) size polymorphism and the poor performance of immunoturbidimetric assays.

[Electrophoresis of serum lipoproteins (lipoproteinogram) with the Hydragel Lipo + Lp(a)® (Sebia) kit: evaluation of Fat Red 7B staining]. / Électrophorèse des lipoprotéines sériques (lipoprotéinogramme) par le kit Hydragel Lipo + Lp(a)® (Sebia) : évaluation de la coloration au Fat Red 7B.

The lipoproteinogram (or lipidogram) consists in an electrophoretic separation of the main classes of serum lipoproteins. Separation was done in agarose gel using the Sebia Hydragel Lipo + Lp(a)® kit. A repeatability study (n=6) was conducted on 3 sera (1 normolipidemic, 1 hypertriglyceridemic and 1 with a high Lp(a) concentration). The reproducibility was studied on these 3 sera and on an ascites liquid containing chylomicrons, upon 6 days (n=6). A quantitative approach was made by studying areas under the curve and percentages of fractions. In both cases (repeatability and reproducibility), the revelation of the lipoproteins in the gel after electrophoretic migration was made either by staining with Sudan Black (procedure recommended by Sebia), or with Fat Red 7B. Regardless of staining, both repeatability and reproducibility studies show that all lipoprotein fractions were correctly detected at their respective positions, leading to satisfactory interpretations of lipoproteinograms. Our reproducibility study also confirmed a good stability of the fractions over 6 days (storage at +5 ± 3̊C). In addition, the Fat Red 7B staining leads to a shorter technical time (about 40 min) for the gel drying and staining/destaining phases, which allows us to respond more quickly to certain urgent requests such as chylothorax diagnosis.

Selective thrombophilia screening of patients with nonarteritic anterior ischemic optic neuropathy.

BACKGROUND: To date, the question whether there is a relationship between thrombophilic disorders and the development of nonarteritic ischemic optic neuropathy (NAION) remains controversial. We sought to investigate the prevalence of various coagulation defects among NAION patients <65 years of age, and to provide clinical guidelines for a selective thrombophilia screening. METHODS: A cohort of 35 patients <65 years of age with NAION and 70 controls matched for age and sex were prospectively screened for thrombophilic risk factors. RESULTS: Overall, thrombophilic defects were found to be present in 18 of 35 patients (51.4%) and in 12 of 70 (17.1%) controls (P = 0.0005). The most frequent coagulation disorders were increased levels of factor VIII (P = 0.015) and lipoprotein (a) (P = 0.005). Patients without cardiovascular risk factors had a statistically significant higher frequency of coagulation disorders than patients with these risk factors (P = 0.0059). There was a strong association of coagulation disorders and a personal or family history of thromboembolism (P = 0.028). Moreover, we determined the age of

Effects of either tibolone or continuous combined transdermal estradiol with medroxyprogesterone acetate on coagulatory factors and lipoprotein(a) in menopause.

BACKGROUND/AIM: The aim of this prospective controlled study was to compare the effects of two therapies for menopause on factor VII (FVII) and hemostatic variables. METHODS: Postmenopausal women were assigned to receive one of the following treatments: transdermal estradiol (TTS E2; 50 microg) combined in a continuous sequential regimen with oral medroxyprogesterone acetate (MPA; 10 mg/day for 12 days) (group A; n = 20), tibolone (2.5 mg/day) (group B; n = 21) or placebo (group C; n = 19). Sixty women completed the 1-year treatment and underwent follow-up examinations after 3, 6 and 12 months. RESULTS: TTS E2/MPA induced various changes in procoagulatory factors. At 12 months, fibrinogen, activated FVII (FVIIa) and coagulative FVII (FVIIc) had increased by 10.7, 12.9 and 3.7%, respectively. Among the fibrinolytic factors, plasminogen and alpha2-antiplasmin increased by 11.3 and 7.2%, respectively. Lipoprotein(a) [Lp(a)] and antithrombin III (ATIII) did not show any significant variation. Tibolone induced some changes toward a more homogeneous antithrombotic profile. Fibrinogen, FVIIa and FVIIc decreased significantly by 7.5, 8.1 and 21.3%, respectively. Plasminogen increased (by 11.8%) and Lp(a) decreased (by 28.4%). ATIII was unchanged with tibolone therapy. CONCLUSION: Our results show that tibolone induces a significant reduction in FVIIc and Lp(a) and a greater enhancement of factors promoting fibrinolysis than the TTS E2/MPA regimen.

Associations of plasma LP(a), Hcy and D-D levels with the subtype of ischemic cerebrovascular disease.

The relevance of LP(a), Hcy, and D-D in ischemic cerebrovascular disease remains undefined. This study aimed to assess the associations of plasma LP(a), Hcy and D-D levels with the subtype of ischemic cerebrovascular disease.Patients with ischemic cerebrovascular disease admitted to the Taixing People's Hospital were retrospectively enrolled from November 2017 to July 2018. Immunoturbidimetry was used to assess 119 LAA, 107 SAO, and 112 TIA patients for plasma LP(a), Hcy, and D-D levels.Plasma LP(a), Hcy, and D-D levels in the large artery atherosclerosis (LAA) group were significantly lower than those of the transient ischemic attack (TIA) group (all P < .05). LP(a), Hcy, and D-D levels were significantly reduced in the SAO group compared with the TIA group (both P < .05). The LAA and SAO groups showed comparable values for all the above parameters (P > .05).LP(a), Hcy, and D-D levels differ according to the subtype of ischemic cerebrovascular disease.

Prevalence of metabolic syndrome and serum marker levels in patients with four subtypes of cerebral infarction in Japan.

In this hospital-based cross-sectional study we investigated differences in the levels of serum atherosclerotic and fibrinolytic markers and the prevalence of metabolic syndrome (MS) among patients with four subtypes of cerebral infarctions. Blood samples were taken from 171 cerebral infarction inpatients to determine the levels of high-sensitivity C-reactive protein, serum total homocysteine, serum plasminogen activator inhibitor 1 and lipoprotein a. Subjects were also screened for MS. Atherothrombotic infarction was most prevalent, followed by lacunar and embolic infarction. The median length of hospital stay was longest for embolic infarcts. There were no statistically significant differences in serum marker concentrations. The proportion of MS varied significantly among the subtypes, and was highest among patients with embolic infarctions with the lowest high density cholesterol levels. MS was most prevalent among patients having undergone embolic events that are reported to have the worst prognoses. Further epidemiologic studies are needed to better understand the characteristics and differences in the etiology of cerebral infarction subtypes.

Distribution of apolipoprotein(a) in the plasma from patients with lipoprotein lipase deficiency and with type III hyperlipoproteinemia. No evidence for a triglyceride-rich precursor of lipoprotein(a).

Lipoprotein(a) consists of a low-density lipoprotein containing apolipoprotein (apo) B-100 and of the genetically polymorphic apo(a). It is not known where and how lipoprotein(a) is assembled and whether there exists a precursor for lipoprotein(a). We have determined the phenotype, concentration, and distribution of apo(a) in plasma from patients with lipoprotein lipase (LPL) deficiency (type I hyperlipoproteinemia, n = 14), in apo E 2/2 homozygotes with type III hyperlipoproteinemia (n = 12) and in controls (n = 16). In the two genetic conditions, there is grossly impaired catabolic conversion of apo B-100-containing precursor lipoproteins to low-density lipoproteins. Considering apo(a) type, the plasma concentration of apo(a) was normal in type III patients but significantly reduced in LPL deficiency. Despite the defects in the catabolism of other apo B-containing lipoproteins, the distribution of apo(a) was only moderately affected in both metabolic disorders, with 66.7% (type I) and 74.7% (type III) being present as the characteristic lipoprotein(a) in the density range of 1.05-1.125 g/ml (controls 81.6%). The remainder was distributed between the triglyceride-rich lipoproteins (type I 12.4%, type III 8.5%, controls 4.7%) and the lipid-poor bottom fraction (type I 19.3%, type III 15.3%, controls 12.6%). In all conditions most apo(a) (57-88%) dissociated from the triglyceride-rich lipoproteins upon recentrifugation and was recovered as lipoprotein(a). These data suggest that lipoprotein(a) is not generated from a triglyceride-rich precursor. Lipoprotein(a) may be secreted directly into plasma or may be formed by preferential binding of secreted apo(a) to existing low-density lipoprotein.