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Effects of soy isoflavones on serum lipids and lipoprotein (a) in peritoneal dialysis patients.
Yari, Z, Tabibi, H, Najafi, I, Hedayati, M, Movahedian, M
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2020;(8):1382-1388
Abstract
BACKGROUND AND AIM Lipid abnormalities are common in peritoneal dialysis (PD) patients and no effective treatment to decrease serum lipoprotein (a) [Lp(a)] in dialysis patients is known so far. Therefore, this research was designed to investigate the effects of soy isoflavone supplement on serum lipids and Lp(a) in PD patients. METHODS & RESULTS In this randomized, double-blind, placebo-controlled trial, 40 PD patients were randomly assigned to either the isoflavone or the placebo group. The patients in the isoflavone group received 100 mg soy isoflavone daily for 8 weeks, whereas the placebo group received corresponding placebos. At baseline and the end of the 8th week, 7 mL of blood was obtained from each patient and serum triglycerides, total cholesterol, low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), and Lp(a) were measured. Serum Lp(a) reduced significantly up to 10% in the isoflavone group at the end of week 8 compared to baseline (P < 0.05), and the reduction was significant in comparison with the placebo group (P < 0.05). Serum HDL-C increased significantly up to 11.5% in the isoflavone group at the end of week 8 compared to baseline (P = 0.05), and the increment was significant in comparison with the placebo group (P < 0.05). There were no significant differences between the two groups in mean changes of serum triglycerides, total cholesterol, and LDL-C. CONCLUSIONS This study indicates that daily administration of 100 mg soy isoflavones reduces serum Lp(a) and increases HDL-C concentration which are two determinants of cardiovascular disease in PD patients. CLINICALTRIALS.GOV: NCT03773029. REGISTRATION NUMBER AND DATE NCT03773029 - 2018.
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Lipoprotein(a) Reduction in Persons with Cardiovascular Disease.
Tsimikas, S, Karwatowska-Prokopczuk, E, Gouni-Berthold, I, Tardif, JC, Baum, SJ, Steinhagen-Thiessen, E, Shapiro, MD, Stroes, ES, Moriarty, PM, Nordestgaard, BG, et al
The New England journal of medicine. 2020;(3):244-255
Abstract
BACKGROUND Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels. METHODS We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx, referred to here as APO(a)-LRx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses). RESULTS The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-LRx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions. CONCLUSIONS APO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.).
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Impact of serum lipoprotein (a) level on coronary plaque progression and cardiovascular events in statin-treated patients with acute coronary syndrome: a yokohama-acs substudy.
Matsushita, K, Hibi, K, Komura, N, Kimura, Y, Matsuzawa, Y, Konishi, M, Maejima, N, Iwahashi, N, Kosuge, M, Ebina, T, et al
Journal of cardiology. 2020;(1):66-72
Abstract
BACKGROUND Lipoprotein (a) [Lp(a)] has been reported to be a residual risk factor in patients who have achieved target lipid levels. The aim of the present study was to investigate the associations of Lp(a) with plaque progression and major cardiovascular events in patients with acute coronary syndromes (ACS). METHODS The Yokohama-ACS study included 102 patients with ACS who underwent intravascular ultrasound (IVUS) at baseline and at 10-month follow-up after percutaneous coronary intervention (PCI). The patients were randomly assigned to receive either moderate- or low-intensity statin therapy. IVUS was performed to measure the plaque volume at non-culprit lesions. We enrolled 76 patients for whom Lp(a) levels at 10-month follow-up were available. RESULTS The patients were divided into 2 groups according whether their Lp(a) levels were ≤20 mg/dl [low Lp(a) group; n = 49] or >20 mg/dl [high Lp(a) group; n = 27]. Baseline characteristics and low-density lipoprotein cholesterol levels at 10-month follow-up were similar in the low Lp(a) group and high Lp(a) group (87 ± 29 mg/dl vs. 93 ± 27 mg/dl, p = 0.42). The low Lp(a) group had significant plaque regression, whereas the high Lp(a) group showed slight plaque progression (-6.8% vs. 2.5%, p = 0.02). Ninety-five percent of the prognostic data were obtained 5 years after PCI. The cumulative event-free survival rate was significantly lower in the high Lp(a) group (p = 0.02; log-rank test). CONCLUSIONS Lp(a) levels may be an alternative predictor of further plaque regression and the likelihood of major adverse cardiovascular events in statin-treated ACS patients.
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Replacing Saturated Fats with Unsaturated Fats from Walnuts or Vegetable Oils Lowers Atherogenic Lipoprotein Classes Without Increasing Lipoprotein(a).
Tindall, AM, Kris-Etherton, PM, Petersen, KS
The Journal of nutrition. 2020;(4):818-825
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BACKGROUND Walnuts have established lipid-/lipoprotein-lowering properties; however, their effect on lipoprotein subclasses has not been investigated. Furthermore, the mechanisms by which walnuts improve lipid/lipoprotein concentrations are incompletely understood. OBJECTIVES We aimed to examine, as exploratory outcomes of this trial, the effect of replacing SFAs with unsaturated fats from walnuts or vegetable oils on lipoprotein subclasses, cholesterol efflux, and proprotein convertase subtilisin/kexin type 9 (PCSK9). METHODS A randomized, crossover, controlled-feeding study was conducted in individuals at risk of cardiovascular disease (CVD) (n = 34; 62% men; mean ± SD age 44 ± 10 y; BMI: 30.1 ± 4.9 kg/m2). After a 2-wk run-in diet (12% SFAs, 7% PUFAs, 12% MUFAs), subjects consumed the following diets, in randomized order, for 6 wk: 1) walnut diet (WD) [57-99 g/d walnuts, 7% SFAs, 16% PUFAs [2.7% α-linolenic acid (ALA)], 9% MUFAs]; 2) walnut fatty acid-matched diet [7% SFAs, 16% PUFAs (2.6% ALA), 9% MUFAs]; and 3) oleic acid replaces ALA diet (ORAD) [7% SFAs, 14% PUFAs (0.4% ALA); 12% MUFAs] (all percentages listed are of total kilocalories ). Serum collected after the run-in (baseline) and each diet period was analyzed for lipoprotein classes and subclasses (vertical auto profile), cholesterol efflux, and PCSK9. Linear mixed models were used for data analysis. RESULTS Compared with the ORAD, total cholesterol (mean ± SEM -8.9± 2.3 mg/dL; -5.1%; P < 0.001), non-HDL cholesterol (-7.4 ± 2.0 mg/dL; -5.4%; P = 0.001), and LDL cholesterol (-6.9 ± 1.9 mg/dL; -6.5%; P = 0.001) were lower after the WD; no other pairwise differences existed. There were no between-diet differences for HDL-cholesterol or LDL-cholesterol subclasses. Lipoprotein(a) [Lp(a)], cholesterol efflux, and PCSK9 were unchanged after the diets. CONCLUSIONS In individuals at risk of CVD, replacement of SFAs with unsaturated fats from walnuts or vegetable oils improved lipid/lipoprotein classes, including LDL-cholesterol, non-HDL cholesterol, and total cholesterol, without an increase in Lp(a). These improvements were not explained by changes in cholesterol efflux capacity or PCSK9. This trial was registered at clinicaltrials.gov as NCT01235832.
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Peripheral Artery Disease and Venous Thromboembolic Events After Acute Coronary Syndrome: Role of Lipoprotein(a) and Modification by Alirocumab: Prespecified Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial.
Schwartz, GG, Steg, PG, Szarek, M, Bittner, VA, Diaz, R, Goodman, SG, Kim, YU, Jukema, JW, Pordy, R, Roe, MT, et al
Circulation. 2020;(20):1608-1617
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BACKGROUND Patients with acute coronary syndrome are at risk for peripheral artery disease (PAD) events and venous thromboembolism (VTE). PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors reduce lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C) levels. Our objective was to ascertain whether PCSK9 inhibition reduces the risk of PAD events or VTE after acute coronary syndrome, and if such effects are related to levels of lipoprotein(a) or LDL-C. METHODS This was a prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome), which was conducted in 18 924 patients with recent acute coronary syndrome on intensive or maximum-tolerated statin treatment who were randomized to the PCSK9 inhibitor alirocumab or placebo. In a prespecified analysis, PAD events (critical limb ischemia, limb revascularization, or amputation for ischemia) and VTE (deep vein thrombosis or pulmonary embolism) were assessed. LDL-C was corrected (LDL-Ccorrected) for cholesterol content in lipoprotein(a). RESULTS At baseline, median lipoprotein(a) and LDL-Ccorrected were 21 and 75 mg/dL, respectively; with alirocumab, median relative reductions were 23.5% and 70.6%, respectively. PAD events and VTE occurred in 246 and 92 patients, respectively. In the placebo group, risk of PAD events was related to baseline quartile of lipoprotein(a) (Ptrend=0.0021), and tended to associate with baseline quartile of LDL-Ccorrected (Ptrend=0.06); VTE tended to associate with baseline quartile of lipoprotein(a) (Ptrend=0.06), but not LDL-Ccorrected (Ptrend=0.85). Alirocumab reduced risk of PAD events (hazard ratio [HR], 0.69 [95% CI, 0.54-0.89]; P=0.004), with nonsignificantly fewer VTE events (HR, 0.67 [95% CI, 0.44-1.01]; P=0.06). Reduction in PAD events with alirocumab was associated with baseline quartile of lipoprotein(a) (Ptrend=0.03), but not LDL-Ccorrected (Ptrend=0.50). With alirocumab, the change from baseline to Month 4 in lipoprotein(a), but not LDL-Ccorrected, was associated with the risk of VTE and the composite of VTE and PAD events. CONCLUSIONS In statin-treated patients with recent acute coronary syndrome, risk of PAD events is related to lipoprotein(a) level and is reduced by alirocumab, particularly among those with high lipoprotein(a). Further study is required to confirm whether risk of VTE is related to lipoprotein(a) level and its reduction with alirocumab. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.
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Plasma kinetics of mature PCSK9, furin-cleaved PCSK9, and Lp(a) with or without administration of PCSK9 inhibitors in acute myocardial infarction.
Nakamura, A, Kanazawa, M, Kagaya, Y, Kondo, M, Sato, K, Endo, H, Nozaki, E
Journal of cardiology. 2020;(4):395-401
Abstract
BACKGROUND There are two types of circulating proprotein convertase subtilisin/kexin type 9 (PCSK9), mature and furin-cleaved. Most types of lipoprotein(a) [Lp(a)], an independent risk factor of cardiovascular events, bind to mature PCSK9. OBJECTIVE This study examined the effects of monoclonal anti-PCSK9 antibody on plasma PCSK9 and Lp(a) levels in acute myocardial infarction (MI). METHODS Acute MI patients (n=36) were randomly divided into evolocumab (140mg; n=17) and non-evolocumab (n=19) groups. Changes in plasma PCSK9 and Lp(a) levels were monitored before and 1, 3, 5, 10, and 20 days after evolocumab administration. RESULTS In the non-evolocumab group, plasma levels of mature PCSK9, furin-cleaved PCSK9, and Lp(a) (236.4±57.3ng/mL, 22.4±5.8ng/mL, and 19.2.±16.5mg/dL, respectively) significantly increased by day 3 (408.8±77.1ng/mL, p<0.001; 47.2±15.7ng/mL, p<0.001; and 39.7±21.3mg/dL, p<0.005, respectively) and returned to the baseline by day 10 or 20. In the evolocumab group, mature PCSK9 significantly increased by >1000ng/mL with a simultaneous decline of furin-cleaved PCSK9 below the measurement sensitivity level after day 3. The incremental area under the curve for plasma Lp(a) levels was significantly smaller in the evolocumab group compared with the non-evolocumab group (p=0.038). CONCLUSION Mature and furin-cleaved PCSK9 are transiently upregulated after MI onset. Evolocumab significantly increases mature PCSK9 and decreases furin-cleaved PCSK9 and might inhibit transient increase of plasma Lp(a) in acute MI.
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Persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment.
Stiekema, LCA, Stroes, ESG, Verweij, SL, Kassahun, H, Chen, L, Wasserman, SM, Sabatine, MS, Mani, V, Fayad, ZA
European heart journal. 2019;(33):2775-2781
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AIMS: Subjects with lipoprotein(a) [Lp(a)] elevation have increased arterial wall inflammation and cardiovascular risk. In patients at increased cardiovascular risk, arterial wall inflammation is reduced following lipid-lowering therapy by statin treatment or lipoprotein apheresis. However, it is unknown whether lipid-lowering treatment in elevated Lp(a) subjects alters arterial wall inflammation. We evaluated whether evolocumab, which lowers both low-density lipoprotein cholesterol (LDL-C) and Lp(a), attenuates arterial wall inflammation in patients with elevated Lp(a). METHODS AND RESULTS In this multicentre, randomized, double-blind, placebo-controlled study, 129 patients {median [interquartile range (IQR)]: age 60.0 [54.0-67.0] years, Lp(a) 200.0 [155.5-301.5] nmol/L [80.0 (62.5-121.0) mg/dL]; mean [standard deviation (SD)] LDL-C 3.7 [1.0] mmol/L [144.0 (39.7) mg/dL]; National Cholesterol Education Program high risk, 25.6%} were randomized to monthly subcutaneous evolocumab 420 mg or placebo. Compared with placebo, evolocumab reduced LDL-C by 60.7% [95% confidence interval (CI) 65.8-55.5] and Lp(a) by 13.9% (95% CI 19.3-8.5). Among evolocumab-treated patients, the Week 16 mean (SD) LDL-C level was 1.6 (0.7) mmol/L [60.1 (28.1) mg/dL], and the median (IQR) Lp(a) level was 188.0 (140.0-268.0) nmol/L [75.2 (56.0-107.2) mg/dL]. Arterial wall inflammation [most diseased segment target-to-background ratio (MDS TBR)] in the index vessel (left carotid, right carotid, or thoracic aorta) was assessed by 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography. Week 16 index vessel MDS TBR was not significantly altered with evolocumab (-8.3%) vs. placebo (-5.3%) [treatment difference -3.0% (95% CI -7.4% to 1.4%); P = 0.18]. CONCLUSION Evolocumab treatment in patients with median baseline Lp(a) 200.0 nmol/L led to a large reduction in LDL-C and a small reduction in Lp(a), resulting in persistent elevated Lp(a) levels. The latter may have contributed to the unaltered arterial wall inflammation.
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Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk.
O'Donoghue, ML, Fazio, S, Giugliano, RP, Stroes, ESG, Kanevsky, E, Gouni-Berthold, I, Im, K, Lira Pineda, A, Wasserman, SM, Češka, R, et al
Circulation. 2019;(12):1483-1492
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BACKGROUND Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined. METHODS Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration. RESULTS The median (interquartile range) baseline Lp(a) concentration was 37 (13-165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4: quartile 1, 1.22; 95% CI, 1.01-1.48) independent of low-density lipoprotein cholesterol. At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%-46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated ( r=0.37; 95% CI, 0.36-0.39; P<0.001). Evolocumab reduced the risk of coronary heart disease death, myocardial infarction, or urgent revascularization by 23% (hazard ratio, 0.77; 95% CI, 0.67-0.88) in patients with a baseline Lp(a) >median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80-1.08; P interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively. CONCLUSIONS Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.
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Serum lipoprotein(a) is not modified by interleukin-6 receptor antagonism or associated with inflammation in non-ST-elevation myocardial infarction.
Ueland, T, Kleveland, O, Michelsen, AE, Wiseth, R, Damås, JK, Holven, KB, Aukrust, P, Gullestad, L, Yndestad, A, Halvorsen, B
International journal of cardiology. 2019;:348-350
Abstract
BACKGROUND The IL-6 receptor antagonist tocilizumab has been shown to attenuate the proatherogenic lipoprotein a [Lp(a)] in rheumatoid arthritis. We evaluated if a single dose of tocilizumab reduced Lp(a) in patients with non-ST-elevation myocardial infarction (NSTEMI). METHODS Lp(a) was assessed by immunoassay (n = 117 patients) at 7 consecutive time-points between day 1 and 3 and at 3 and 6 months follow-up. RESULTS Tocilizumab did not affect Lp(a) at any time-point during the study and was not associated with cardiovascular risk factors. CONCLUSIONS Short-time inhibition of IL-6 with tocilizumab in patients with NSTEMI did not influence Lp(a) levels.
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Lp(a) (Lipoprotein(a)) Levels Predict Progression of Carotid Atherosclerosis in Subjects With Atherosclerotic Cardiovascular Disease on Intensive Lipid Therapy: An Analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) Carotid Magnetic Resonance Imaging Substudy-Brief Report.
Hippe, DS, Phan, BAP, Sun, J, Isquith, DA, O'Brien, KD, Crouse, JR, Anderson, T, Huston, J, Marcovina, SM, Hatsukami, TS, et al
Arteriosclerosis, thrombosis, and vascular biology. 2018;(3):673-678
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OBJECTIVE To assess whether Lp(a) (lipoprotein(a)) levels and other lipid levels were predictive of progression of atherosclerosis burden as assessed by carotid magnetic resonance imaging in subjects who have been treated with LDL-C (low-density lipoprotein cholesterol)-lowering therapy and participated in the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes). APPROACH AND RESULTS AIM-HIGH was a randomized, double-blind study of subjects with established vascular disease, elevated triglycerides, and low HDL-C (high-density lipoprotein cholesterol). One hundred fifty-two AIM-HIGH subjects underwent both baseline and 2-year follow-up carotid artery magnetic resonance imaging. Plaque burden was measured by the percent wall volume (%WV) of the carotid artery. Associations between annualized change in %WV with baseline and on-study (1 year) lipid variables were evaluated using multivariate linear regression and the Bonferroni correction to account for multiple comparisons. Average %WV at baseline was 41.6±6.8% and annualized change in %WV over 2 years ranged from -3.2% to 3.7% per year (mean: 0.2±1.1% per year; P=0.032). Increases in %WV were significantly associated with higher baseline Lp(a) (β=0.34 per 1-SD increase of Lp(a); 95% confidence interval, 0.15-0.52; P<0.001) after adjusting for clinical risk factors and other lipid levels. On-study Lp(a) had a similar positive association with %WV progression (β=0.33; 95% confidence interval, 0.15-0.52; P<0.001). CONCLUSIONS Despite intensive lipid therapy, aimed at aggressively lowering LDL-C to <70 mg/dL, carotid atherosclerosis continued to progress as assessed by carotid magnetic resonance imaging and that elevated Lp(a) levels were independent predictors of increases in atherosclerosis burden.