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MEDI6012: Recombinant Human Lecithin Cholesterol Acyltransferase, High-Density Lipoprotein, and Low-Density Lipoprotein Receptor-Mediated Reverse Cholesterol Transport.
George, RT, Abuhatzira, L, Stoughton, SM, Karathanasis, SK, She, D, Jin, C, Buss, NAPS, Bakker-Arkema, R, Ongstad, EL, Koren, M, et al
Journal of the American Heart Association. 2021;(13):e014572
Abstract
Background MEDI6012 is recombinant human lecithin cholesterol acyltransferase, the rate-limiting enzyme in reverse cholesterol transport. Infusions of lecithin cholesterol acyltransferase have the potential to enhance reverse cholesterol transport and benefit patients with coronary heart disease. The purpose of this study was to test the safety, pharmacokinetic, and pharmacodynamic profile of MEDI6012. Methods and Results This phase 2a double-blind study randomized 48 subjects with stable coronary heart disease on a statin to a single dose of MEDI6012 or placebo (6:2) (NCT02601560) with ascending doses administered intravenously (24, 80, 240, and 800 mg) and subcutaneously (80 and 600 mg). MEDI6012 demonstrated rates of treatment-emergent adverse events that were similar to those of placebo. Dose-dependent increases in high-density lipoprotein cholesterol were observed with area under the concentration-time curves from 0 to 96 hours of 728, 1640, 3035, and 5318 should be: mg·h/mL in the intravenous dose groups and 422 and 2845 mg·h/mL in the subcutaneous dose groups. Peak mean high-density lipoprotein cholesterol percent change was 31.4%, 71.4%, 125%, and 177.8% in the intravenous dose groups and 18.3% and 111.2% in the subcutaneous dose groups, and was accompanied by increases in endogenous apoA1 (apolipoprotein A1) and non-ATP-binding cassette transporter A1 cholesterol efflux capacity. Decreases in apoB (apolipoprotein B) were observed across all dose levels and decreases in atherogenic small low-density lipoprotein particles by 41%, 88%, and 79% at the 80-, 240-, and 800-mg IV doses, respectively. Conclusions MEDI6012 demonstrated an acceptable safety profile and increased high-density lipoprotein cholesterol, endogenous apoA1, and non-ATP-binding cassette transporter A1 cholesterol efflux capacity while reducing the number of atherogenic low-density lipoprotein particles. These findings are supportive of enhanced reverse cholesterol transport and a functional high-density lipoprotein phenotype. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601560.
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Adverse risk factor trends limit gains in coronary heart disease mortality in Barbados: 1990-2012.
Sobers, NP, Unwin, N, Samuels, TA, Capewell, S, O'Flaherty, M, Critchley, JA
PloS one. 2019;(4):e0215392
Abstract
BACKGROUND Although most countries face increasing population levels of obesity and diabetes their effect on coronary heart disease (CHD) mortality has not been often studied in small island developing states (SIDs) where obesity rates are among the highest in the world. We estimated the relative contributions of treatments and cardiovascular risk factors to the decline in CHD mortality from 1990 to 2012 in the Caribbean island, Barbados. METHODS We used the IMPACT CHD mortality model to estimate the effect of increased coverage of effective medical/surgical treatments and changes in major CHD risk factors on mortality trends in 2012 compared with 1990. We calculated deaths prevented or postponed (DPPs) for each model risk factor and treatment group. We obtained data from WHO Mortality database, population denominators from the Barbados Statistical Service stratified by 10-year age group (ages 25-34 up to 85 plus), population-based risk factor surveys, Global Burden of Disease and Barbados' national myocardial infarction registry. Monte Carlo probabilistic sensitivity analysis was performed. RESULTS In 1990 the age-standardized CHD mortality rate was 109.5 per 100,000 falling to 55.3 in 2012. Implementation of effective treatment accounted for 56% DPPs (95% (Uncertainty Interval (UI) 46%, 68%), mostly due to the introduction of treatments immediately after acute myocardial infarction (AMI) (14%) and unstable angina (14%). Overall, risk factors contributed 19% DPPs (95% UI 6% to 34%) mostly attributed to decline in cholesterol (18% DPPs, 95% UI 12%, 26%). Adverse trends in diabetes: 14% additional deaths(ADs) 95% UI 8% to 21% ADs) and BMI (2% ADs 95%UI 0 to 5% ADs) limited potential for risk factor gains. CONCLUSIONS Given the significant negative impact of obesity/diabetes on mortality in this analysis, research that explores factors affecting implementation of evidenced-based preventive strategies is needed. The fact that most of the decline in CHD mortality in Barbados was due to treatment provides an example for SIDs about the advantages of universal access to care and treatment.
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Cholesterol efflux capacity, HDL cholesterol, and risk of coronary heart disease: a nested case-control study in men.
Cahill, LE, Sacks, FM, Rimm, EB, Jensen, MK
Journal of lipid research. 2019;(8):1457-1464
Abstract
The capacity of HDLs to accept cholesterol effluxing from macrophages has been proposed as a new biomarker of HDLs' anti-atherogenic function. Whether cholesterol efflux capacity (CEC) is independent of HDL cholesterol (HDL-C) as a biomarker for coronary heart disease (CHD) risk in a generally healthy primary-prevention population remains unanswered. Therefore, in this nested case-control study, we simultaneously assessed CEC (using J774 cells) and plasma HDL-C levels as predictors of CHD in healthy middle-aged and older men not receiving treatment affecting blood lipid concentrations. We used risk-set sampling of participants free of disease at baseline from the Health Professionals Follow-Up Study, and matched cases (n = 701) to controls 1:1 for age, smoking, and blood sampling date. We applied conditional logistic regression models to calculate the multivariable relative risk and 95% CIs of CHD over 16 years of follow-up. CEC and HDL-C were correlated (r = 0.50, P < 0.0001). The risk (95% CI) of CHD per one SD higher CEC was 0.82 (0.71-0.96), but completely attenuated to 1.08 (0.85-1.37) with HDL-C in the model. The association per one SD between HDL-C and CHD (0.66; 0.58-0.76) was essentially unchanged (0.68; 0.53-0.88) after adjustment for CEC. These findings indicate that CEC's ability to predict CHD may not be independent of HDL-C in a cohort of generally healthy men.
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Prospective multi-center registry to evaluate efficacy and safety of the newly developed diamond-like carbon-coated cobalt-chromium coronary stent system.
Ando, K, Ishii, K, Tada, E, Kataoka, K, Hirohata, A, Goto, K, Kobayashi, K, Tsutsui, H, Nakahama, M, Nakashima, H, et al
Cardiovascular intervention and therapeutics. 2017;(3):225-232
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Abstract
The purpose of this multi-center, non-randomized, and open-label clinical trial was to determine the non-inferiority of diamond-like carbon (DLC)-coated cobalt-chromium coronary stent, the MOMO DLC coronary stent, relative to commercially available bare-metal stents (MULTI-LINK VISION®). Nineteen centers in Japan participated. The study cohort consisted of 99 patients from 19 Japanese centers with single or double native coronary vessel disease with de novo and restenosis lesions who met the study eligibility criteria. This cohort formed the safety analysis set. The efficacy analysis set consisted of 98 patients (one case was excluded for violating the eligibility criteria). The primary endpoint was target vessel failure (TVF) rate at 9 months after stent placement. Of the 98 efficacy analysis set patients, TVF occurred in 11 patients (11.2 %, 95 % confidence interval 5.7-19.2 %) at 9 months after the index stent implantation. The upper 95 % confidence interval for TVF of the study stent was lower than that previously reported for the commercially available MULTI-LINK VISION® (19.6 %), demonstrating non-inferiority of the study stent to MULTI-LINK VISION®. All the TVF cases were related to target vascular revascularization. None of the cases developed in-stent thrombosis or myocardial infarction. The average in-stent late loss and binary restenosis rate at the 6-month follow-up angiography were 0.69 mm and 10.5 %, respectively, which are lower than the reported values for commercially available bare-metal stents. In conclusion, the current pivotal clinical study evaluating the new MOMO DLC-coated coronary stent suggested its low rates of TVF and angiographic binary restenosis, and small in-stent late loss, although the data were considered preliminary considering the small sample size and single arm study design.
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Intravenous iron isomaltoside 1000 (Monofer®) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: a randomized double-blind placebo-controlled clinical trial (the PROTECT trial).
Johansson, PI, Rasmussen, AS, Thomsen, LL
Vox sanguinis. 2015;(3):257-66
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BACKGROUND AND OBJECTIVES This trial explores whether intravenous iron isomaltoside 1000 (Monofer®) results in a better regeneration of haemoglobin levels and prevents anaemia compared to placebo in preoperative non-anaemic patients undergoing cardiac surgery. STUDY DESIGN AND METHODS The trial is a prospective, double-blind, comparative, placebo-controlled trial of 60 non-anaemic patients undergoing cardiac surgery. The patients were randomized 1:1 to either 1000 mg intravenous iron isomaltoside 1000 administered perioperatively by infusion or placebo. RESULTS Mean preoperative haemoglobin in the active treatment group was 14·3 g/dl vs. 14·0 g/dl in the placebo group. At discharge 5 days after surgery, haemoglobin levels were reduced to 10·7 and 10·5 g/dl, respectively. One month after surgery, haemoglobin concentration had increased to an average of 12·6 g/dl vs. 11·8 g/dl (p = 0·012) and significantly more patients were non-anaemic in the intravenous iron isomaltoside 1000-treated group compared to the placebo group (38·5% vs. 8·0%; p = 0·019). There were no differences in side-effects between the groups. CONCLUSION A single perioperative 1000 mg dose of intravenous iron isomaltoside 1000 significantly increased the haemoglobin level and prevented anaemia 4 weeks after surgery, with a short-term safety profile similar to placebo. Future trials on potential clinical benefits of preoperative treatment with intravenous iron in non-anaemic patients are needed.
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A pro-atherogenic HDL profile in coronary heart disease patients: an iTRAQ labelling-based proteomic approach.
Yan, LR, Wang, DX, Liu, H, Zhang, XX, Zhao, H, Hua, L, Xu, P, Li, YS
PloS one. 2014;(5):e98368
Abstract
OBJECTIVES This study aims to compare the protein composition of high-density lipoprotein (HDL) particles in coronary heart disease (CHD) patients and controls by proteomic methods. BACKGROUND HDL has been reported to exert pro-atherogenic properties in CHD patients. Accumulating evidence indicates that HDL composition, rather than the HDL-C level, determines its functions. The changes in HDL composition involved in the conversion of anti-atherogenic to pro-atherogenic properties in CHD patients are currently unknown. METHODS AND RESULTS iTRAQ combined with nanoLC-MS/MS was performed to obtain a differential expression profile of the HDL pooled samples of the male age-matched CHD patients and controls (n = 10/group). Of the 196 proteins identified in the examined HDL, 12 were differentially expressed between the CHD patients and the controls, including five up-regulated proteins and seven down-regulated proteins. Using GO analysis, we determined that the up-regulated proteins were mostly involved in inflammatory reactions, displaying a potential pro-atherogenic profile. In contrast, the down-regulated proteins were mostly involved in lipid metabolism processes, displaying anti-atherogenic properties. To confirm the proteomic results, serum amyloid A (SAA) and apoC-I were selected and quantified by ELISA, in the same population as the proteomic analysis, as well as another independent population (n = 120/group). Consistent with the proteomic results, the amount of SAA was significantly increased, and apoC-I was significantly decreased in the HDL particles of CHD patients compared with those of controls (P<0.05). CONCLUSIONS Our study shows that the HDL proteome changes to a pro-atherogenic profile in CHD patients, which might compromise the protective effects of HDL. Proteomic analysis of HDL composition may provide more relevant information regarding their functional properties than steady-state HDL-C levels.
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Effects of simvastatin/ezetimibe on microparticles, endothelial progenitor cells and platelet aggregation in subjects with coronary heart disease under antiplatelet therapy.
Camargo, LM, França, CN, Izar, MC, Bianco, HT, Lins, LS, Barbosa, SP, Pinheiro, LF, Fonseca, FA
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2014;(5):432-7
Abstract
It is not known whether the addition of ezetimibe to statins adds cardiovascular protection beyond the expected changes in lipid levels. Subjects with coronary heart disease were treated with four consecutive 1-week courses of therapy (T) and evaluations. The courses were: T1, 100 mg aspirin alone; T2, 100 mg aspirin and 40 mg simvastatin/10 mg ezetimibe; T3, 40 mg simvastatin/10 mg ezetimibe, and 75 mg clopidogrel (300 mg initial loading dose); T4, 75 mg clopidogrel alone. Platelet aggregation was examined in whole blood. Endothelial microparticles (CD51), platelet microparticles (CD42/CD31), and endothelial progenitor cells (CD34/CD133; CDKDR/CD133, or CD34/KDR) were quantified by flow cytometry. Endothelial function was examined by flow-mediated dilation. Comparisons between therapies revealed differences in lipids (T2 and T3
T1 and T4, P=0.001). Decreased platelet aggregation was observed after aspirin (arachidonic acid, T1
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Reactivity of direct assays for low-density lipoprotein (LDL) cholesterol toward charge-modified LDL in hypercholesterolemia.
Zhang, B, Kawachi, E, Matsunaga, A, Imaizumi, S, Noda, K, Uehara, Y, Miura, S, Yoshinaga, K, Kuroki, M, Saku, K
Circulation journal : official journal of the Japanese Circulation Society. 2012;(9):2241-8
Abstract
BACKGROUND The aim of the present study was to compare 2 direct measurements for low-density lipoprotein cholesterol (LDL-C) with the Friedewald calculation (LDL-C [F]) in serum and their relationship with size-and charge-based LDL subfractions in serum ultracentrifugation fractions in patients with hypercholesterolemia (HC). METHODS AND RESULTS Serum samples from 283 HC patients who participated in a statin trial (the PATROL trial) were analyzed. Homogeneous assays for LDL-C were performed using reagents from Sekisui Medical (LDL-C [Se]) and Kyowa Medex (LDL-C [Ky]). Charge-based LDL subfractions were analyzed by capillary isotachophoresis (cITP). In whole serum in HC patients at baseline, LDL-C (Se) and LDL-C (Ky) negatively and positively deviated, respectively, from LDL-C (F). The negative deviation of LDL-C (Se) from LDL-C (F) increased with increasing LDL-C, while the positive deviation of LDL-C (Ky) from LDL-C (F) was positively correlated with charge-modified LDL (cmLDL) as analyzed by cITP. In serum d>1.006 g/ml and >1.040 g/ml fractions (LDL and small, dense LDL fractions, respectively), the deviation of LDL-C (Ky) from LDL-C (Se) was positively correlated with LDL-apoB (the number of LDL particles) and cmLDL. CONCLUSIONS The 2 homogenous assays for LDL-C differed with regard to reactivity toward LDL particles and cmLDL in patients with HC. Direct measurement of LDL-C that reflects modified LDL, could be a better marker for the risk of coronary heart disease.
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SLCO1B1 521T-->C functional genetic polymorphism and lipid-lowering efficacy of multiple-dose pravastatin in Chinese coronary heart disease patients.
Zhang, W, Chen, BL, Ozdemir, V, He, YJ, Zhou, G, Peng, DD, Deng, S, Xie, QY, Xie, W, Xu, LY, et al
British journal of clinical pharmacology. 2007;(3):346-52
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AIMS: Pravastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which is widely used both in primary and secondary prevention of coronary heart disease (CHD). Pravastatin is not subject to metabolism by cytochrome P450s, but it is actively transported from blood into target tissues (e.g. hepatocytes in the liver) by the organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1. The aim of the present study was to evaluate the impact of SLCO1B1 521T-->C (Val174Ala) functional genetic polymorphism on the lipid-lowering efficacy of multiple-dose pravastatin in Chinese patients with CHD. METHODS Forty-five hospitalized patients with CHD prospectively received pravastatin as a single-agent therapy (20 mg day(-1) p.o.) for 30 days. Serum triglycerides, total cholesterol, low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol concentrations were determined before and after pravastatin treatment. RESULTS Pravastatin treatment significantly decreased plasma lipids in all patients (P < 0.001). Importantly, we showed an attenuated pravastatin pharmacodynamic effect on total cholesterol in patients with 521TC heterozygote genotype (from 5.52 +/- 0.51 mmol l(-1) to 4.70 +/- 0.35 mmol l(-1), % change -14.5 +/- 6.6%, N = 9) compared with 521TT homozygote genotype (from 5.47 +/- 1.15 mmol l(-1) to 4.21 +/- 0.89 mmol l(-1), % change -22.4 +/- 10.3%, N = 36) (mean +/- SD, P = 0.03, two-tailed test with alpha set at 5%). SLCO1B1 521T-->C functional polymorphism did not significantly influence pravastatin pharmacodynamics on other plasma lipids (P > 0.05). CONCLUSIONS The 521T-->C polymorphism of SLCO1B1 appears to modulate significantly the total cholesterol-lowering efficacy of pravastatin in Chinese patients with CHD. Further studies are warranted to determine the extent to which SLCO1B1 genetic variation may contribute to resistance to pravastatin in Asian patients treated with standard doses of pravastatin.
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Analytical performance and diagnostic accuracy of immunometric assays for the measurement of circulating oxidized LDL.
Holvoet, P, Macy, E, Landeloos, M, Jones, D, Jenny, NS, Van de Werf, F, Tracy, RP
Clinical chemistry. 2006;(4):760-4
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BACKGROUND Oxidized LDL (ox-LDL) plays an important role in the pathogenesis of coronary heart disease (CHD). Several tests for circulating ox-LDL have been published. We believe it is critical to carefully evaluate these assays because small differences in performance may have profound effects when results are compared; we therefore compared the analytical and clinical performances of 2 assays: one developed in our laboratory and a commercial assay (Mercodia) that uses the same monoclonal antibody (4E6). METHODS We determined the variance of ox-LDL in both tests, including its longitudinal stability (n = 225; 3 time points per person) and its diagnostic accuracy, by ROC analysis of 95 consecutive CHD patients and 20 controls. RESULTS The between-person variability was 77% for the in-house assay (with the remaining 23% being within-person and analytical variance) and 74% for the commercial assay. For comparison, previously reported values were 66% for high-sensitivity C-reactive protein and 82% for total cholesterol. The areas under the curves for CHD in the 2 assays were identical (0.85). The odds ratios (logistic regression) for CHD among persons with high ox-LDL (>or=15 mg/L) compared with persons with low ox-LDL were not different: 4.3 (95% confidence interval, 1.4-12) for the in-house assay and 3.3 (1.1-10) for the commercial assay. CONCLUSIONS The longitudinal stability of ox-LDL, as assessed by multiple measures in people over time, is similar to that of total cholesterol and high-sensitivity C-reactive protein. Both assays tested similarly distinguish between healthy controls and CHD patients.