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Posts Tagged ‘High-density lipoprotein’


LDL, HDL, TG, ApoA1 and ApoB: Genetic Loci Associated With Plasma Concentration of these Biomarkers – A Genome-Wide Analysis With Replication

Reporter: Aviva Lev-Ari, PhD, RN

Genetic Loci Associated With Plasma Concentration of Low-Density Lipoprotein Cholesterol, High-Density Lipoprotein Cholesterol, Triglycerides, Apolipoprotein A1, and Apolipoprotein B Among 6382 White Women in Genome-Wide Analysis With Replication

Daniel I. Chasman, PhD*Guillaume Paré, MD, MS*Robert Y.L. Zee, PhD, MPH, Alex N. Parker, PhD, Nancy R. Cook, ScD, Julie E. Buring, ScD, David J. Kwiatkowski, MD, PhD, Lynda M. Rose, MS, Joshua D. Smith, BS, Paul T. Williams, PhD, Mark J. Rieder, PhD, Jerome I. Rotter, MD, Deborah A. Nickerson, PhD, Ronald M. Krauss, MD,Joseph P. Miletich, MD and Paul M Ridker, MD, MPH

Author Affiliations

From the Center for Cardiovascular Disease Prevention (D.I.C., G.P., R.Y.L.Z., N.R.C., J.E.B., L.M.R., P.M.R.) and Donald W. Reynolds Center for Cardiovascular Research (D.I.C., G.P., R.Y.L.Z., N.R.C., D.J.K., P.M.R.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Amgen, Inc, Cambridge, Mass (A.N.P., J.M.P.); Department of Genome Sciences, University of Washington, Seattle, Wash (J.D.S., M.J.R., D.A.N.); Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, Calif (P.T.W., R.M.K.); Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, Calif (J.I.R.); and Children’s Hospital Oakland Research Institute, Oakland, Calif (R.M.K.).

Correspondence to Daniel I. Chasman, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, 900 Commonwealth Ave E, Boston, MA 02215. E-mail dchasman@rics.bwh.harvard.edu

Abstract

Background— Genome-wide genetic association analysis represents an opportunity for a comprehensive survey of the genes governing lipid metabolism, potentially revealing new insights or even therapeutic strategies for cardiovascular disease and related metabolic disorders.

Methods and Results— We have performed large-scale, genome-wide genetic analysis among 6382 white women with replication in 2 cohorts of 970 additional white men and women for associations between common single-nucleotide polymorphisms and low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein (Apo) A1, and ApoB. Genome-wide associations (P<5×10−8) were found at the PCSK9 gene, the APOB gene, the LPLgene, the APOA1-APOA5 locus, the LIPC gene, the CETP gene, the LDLR gene, and the APOE locus. In addition, genome-wide associations with triglycerides at the GCKRgene confirm and extend emerging links between glucose and lipid metabolism. Still other genome-wide associations at the 1p13.3 locus are consistent with emerging biological properties for a region of the genome, possibly related to the SORT1 gene. Below genome-wide significance, our study provides confirmatory evidence for associations at 5 novel loci with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglycerides reported recently in separate genome-wide association studies. The total proportion of variance explained by common variation at the genome-wide candidate loci ranges from 4.3% for triglycerides to 12.6% for ApoB.

Conclusion— Genome-wide associations at the GCKR gene and near the SORT1gene, as well as confirmatory associations at 5 additional novel loci, suggest emerging biological pathways for lipid metabolism among white women.

 SOURCE:

Circulation: Cardiovascular Genetics.2008; 1: 21-30

doi: 10.1161/ CIRCGENETICS.108.773168

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Curator: Aviva Lev-Ari, PhD, RN

 

UPDATED on 7/29/2018

 

HDL-C: Is It Time to Stop Calling It the ‘Good’ Cholesterol? – Medscape – Jul 27, 2018.

 

In Eli Lilly’s Pipeline: DISCONTINUING Evacetrapib, a CETP inhibitor that’s meant to boost HDL

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/10/12/in-eli-lillys-pipeline-discontinuing-evacetrapib-a-cetp-inhibitor-thats-meant-to-boost-hdl/

 

On April 3, 2012 we published

Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore

ACP-501, a recombinant human lecithin-cholesterol acyltransferase (LCAT) enzyme.

LCAT, an enzyme in the bloodstream, is a key component in the reverse cholesterol transport (RCT) system, which is thought to play a major role in driving the removal of cholesterol from the body and may be critical in the management of high-density lipoprotein (HDL) cholesterol levels.  The LCAT enzyme could also play a role in a rare, hereditary disorder called familial LCAT deficiency (FLD) in which the LCAT enzyme is absent.

https://pharmaceuticalintelligence.com/2013/04/03/fight-against-atherosclerotic-cardiovascular-disease-a-biologics-not-a-small-molecule-recombinant-human-lecithin-cholesterol-acyltransferase-rhlcat-attracted-astrazeneca-to-acquire-alphacore/

On April 4, 2013, the next day, a new study was published on a novel class of compounds, cholesteryl ester transfer protein (CETP) inhibitors, has demonstrated many potentially beneficial lipid-modifying effects was published on Anacetrapib, a compound that causes near-complete CETP inhibition, has among its effects, robust reductions in LDL-C and lipoprotein(a) as well as dramatic increases in HDL-C. The ability of anacetrapib to reduce coronary disease events is being tested in the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial (NCT01252953).

Writer’s VIEWS:

    • AstraZeneca acquisition of AlphaCore represents its market entry into the CETP inhibitor segment via an acquisition where the company did not have presence or inhouse research. The results of the second study will position Merck at a superior position upon completion of Phase III Clinical Trials for Anacetrapib
    • If Biologics will help increase HDL in wide market penetration, the market share of Statins will be negatively impacted. Patent expiration and generic market availability of Statin erode future profits
    • Anacetrapib in in Phase III clinical Trial, if successfully completed — will be the FIRST biologics to use CETP inhibition biology of lipid metabolism in the quest to fight atherosclerosis by improving CVD outcomes
    • A connection between this two events and cites in Disclosure, AstraZeneca, Merck, supporting the research of Christopher P Cannon on the study on Anacetrapib.
    • Full Article PDF file was published in Research Reports in Clinical Cardiology, one of the Journals on Beall’s list publisher, where scientists pay to have the article been published, Dove Press, on its Web site says, “There are no limits on the number or size of the papers we can publish.” See reference for Beall’s list publishers http://www.nytimes.com/2013/04/08/health/for-scientists-an-exploding-world-of-pseudo-academia.html?pagewanted=1&_r=0&emc=eta1

Study Goals:

  • testing the hypothesis that CETP inhibition may reduce atherosclerotic outcomes. 
  • answer important questions regarding the role of CETP in the biology of lipid metabolism and atherosclerosis.

Research Reports in Clinical Cardiology, 4 April 2013 Volume 2013:4 Pages 39 – 53

Dylan L Steen,1 Amit V Khera,2 Christopher P Cannon1

1TIMI Study Group, Cardiovascular Division, 2Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

Disclosure

Dr Cannon is a member of the advisory boards of and has received grant support from Alnylam, Bristol-Myers Squibb, Pfizer, and CSL Behring; has received grant support from Accumetrics, AstraZeneca, Essentialis, GlaxoSmithKline, Merck, Regeneron, Sanofi, and Takeda; and is a clinical advisor to Automated Medical Systems. All other authors have reported that they have no relationships relevant to the contents of this paper.

Abstract: Despite major advances in cardiovascular care in recent decades, atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Statins have been shown to reduce cardiovascular events by 25%–40% in a dose-dependent fashion; yet additional therapies are needed to reduce vascular disease progression and acute thrombotic events. In addition to low-density lipoprotein cholesterol (LDL-C) reduction, other lipid risk factors, such as low high-density lipoprotein cholesterol (HDL-C), have created interest as therapeutic targets to lower cardiovascular risk. However, the absence of compelling data for incremental benefit of non-LDL-centric therapies in the statin era has limited their clinical use. A novel class of compounds, cholesteryl ester transfer protein (CETP) inhibitors, has demonstrated many potentially beneficial lipid-modifying effects. While in vitro and animal data for CETP inhibition have been encouraging, the initial enthusiasm for the class has been tempered by the failure of two CETP inhibitors (torcetrapib and dalcetrapib) in Phase III trials to reduce cardiovascular outcomes. Anacetrapib, a compound that causes near-complete CETP inhibition, has among its effects, robust reductions in LDL-C and lipoprotein(a) as well as dramatic increases in HDL-C. The ability of anacetrapib to reduce coronary disease events is being tested in the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial (NCT01252953).

Keywords: anacetrapib, cholesteryl ester transfer protein, cholesteryl ester transfer protein inhibitor, atherosclerosis

  • Niacin, which augments HDL-C by 20%–25%, recently failed to lower atherosclerotic events in both the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH)6 and Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials.7,8
  • Lp(a) lowering has not yet been evaluated in randomized controlled trials, but observational and genetic (including Mendelian randomization) analyses have demonstrated an independent association of increased Lp(a) levels with increased CV events, suggesting Lp(a) lowering may confer benefit.9
  • surprising failure of the first two CETP inhibitors (torcetrapib and dalcetrapib) in Phase III outcomes trials has somewhat tempered this initial excitement and forced a re-evaluation of the complex effects of CETP inhibition on lipid metabolism and vascular biology.
  • Anacetrapib results in near-complete CETP inhibition with more pronounced lipid effects than its predecessors and is currently in a Phase III study for secondary prevention of coronary events. If successful it is likely that anacetrapib will also be considered for statin-intolerant patients and for primary prevention in patients who require LDL-C lowering beyond statin monotherapy
  • Human CETP is a 476-residue, 74 kDa, hydrophobic glycoprotein primarily secreted by the liver and adipose tissue.13 CETP was first cloned in 1987.14 The structure of CETP allows formation of a tunnel with the opening on one end interacting with HDL and the other with a very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), or LDL particle. The hydrophobic central cavity of this tunnel is large enough to allow transfer of neutral lipids (eg, cholesteryl esters [CEs], triglycerides [TGs]) from donor to acceptor particles, but conformational changes may occur to accommodate larger lipoprotein particles. The concave surface of CETP matches the curvature of the HDL particles to which it is primarily bound in the bloodstream.15,16
  • The overall effect of CETP is a net transfer of CE from HDL to these apolipoprotein B (apoB)-containing particles and TG to HDL and LDL
  • An important driver of the transfer of CE from HDL to apoB-containing particles is the production of CE from free cholesterol within HDL by lecithin acetyltransferase (LCAT).17

    The role of CETP in reverse cholesterol transport.

    Beginning in the peripheral tissues, free cholesterol is predominantly taken up by small “immature” HDL particles (eg, pre-β-HDL) via the ABCA1 transporter. Alternatively, it can be taken up by larger “mature” HDL particles (eg, HDL2) via the ABCG1 transporter. LCAT converts free cholesterol into cholesteryl ester, which is then shuttled to apoB-lipoproteins (eg, LDL, VLDL) in exchange for triglycerides. Only a minority of cholesteryl ester is delivered directly to the liver by HDL via the SR-BI; the majority is delivered indirectly to the liver by apoB-lipoproteins via the LDL recepter.

    Abbreviations: CETP, cholesteryl ester transfer protein; HDL, high-density lipoprotein; ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; LCAT, lecithin acetyltransferase; apoB, apolipoprotein B; LDL, low-density lipoprotein; VLDL, very low density lipoprotein; SR-BI, scavenger receptor-BI; FC, free cholesterol; CE, cholesteryl ester.

  • One of the interesting questions in CETP deficiency is whether the HDL particles produced by potent CETP inhibition are functional. Regardless of whether reverse cholesterol transport is increased, the initial steps of cholesterol efflux from foam cells may be one of the key anti-atherogenic functions of HDL.5
  • This increased efflux is related to the very high content of LCAT and apoE in these large HDL particles, presumably driving net cholesterol efflux by promoting cholesterol esterification.36
  • effect of CETP deficiency on liver uptake of cholesteryl ester, an important downstream step in a reverse cholesterol transport. These studies suggest that there may be increased CE uptake via SR-BI as well as through a high affinity of large apoE-rich HDL for LDL receptors.20
  • meta-analysis established that three CETP genotypes were not only associated with decreased CETP activity and increased HDL but also with a lower risk of myocardial infarction (MI). For example, for each allele inherited, individuals with the TaqIB polymorphism had lower mean CETP activity (−8.6%), higher mean HDL-C (4.5%), higher mean apoA-I (2.4%), and an odds ratio for coronary disease of 0.95 (95% confidence intervals [CI], 0.92, 0.99). Similar associations were found for the other two CETP genotypes.40
  • Subsequent studies have confirmed that genetic variants leading to reduced CETP activity and its corresponding anti-atherogenic lipid profile are associated with reduced atherosclerotic outcomes.41–43
  • In ILLUSTRATE, an inverse association between HDL-C achieved and the primary endpoint of atheroma volume (r = −0.17, P , 0.001) was found. In addition, the highest quartile of HDL-C achieved (.86 mg/dL) demonstrated atheroma regression, suggesting that there may be a “threshold effect” to HDL-C elevation.68
  • Other CETP inhibitors:

Dalcetrapib
was developed by Hoffmann–La Roche until May 2012. It did not raise blood pressure and did raise HDL, but it showed no clinically meaningful efficacy.

Evacetrapib 

is under development by Eli Lilly & Company.
Torcetrapib
was developed by Pfizer until December 2006 but caused unacceptable increases in blood pressure and had net cardiovascular detriment.
Anacetrapib At the 16th International Symposium on Drugs Affecting Lipid Metabolism (New York, Oct 4-7, 2007), Merck reported on a Phase IIb study. The eight week study reported dosage correlated reduction in LDL-C and increases in HDL-C levels with no corresponding increases in blood pressure in any cohort. The increase in HDL was particularly significant, averaging 44 percent, 86 percent, 139 percent and 133 percent at doses of 10 mg, 40 mg, 150 mg and 300 mg. Merck performed a dose-ranging study of anacetrapib, with the results presented in 2009.

Anacetrapib 

Anacetrapib is a 3,5-bis-trifluoromethyl-benzene derivative with similar binding properties to CETP as torcetrapib. The compound was developed when it was found that a substitution modification of the oxazolidinone ring increased its potency for CETP inhibition in a transgenic mouse model.85 In terms of its pharmacokinetics and pharmacodynamics, anacetrapib is rapidly absorbed with a time-to-peak plasma concentration of about 4 hours. The oral bioavailability of anacetrapib is poor, with only about 20% being absorbed; however at this exposure, LDL-C is reduced up to 40% and HDL-C increased up to 140%. It is recommended that anacetrapib be taken with food (ie, low-fat diet) to increase drug exposure (and efficacy) as well as compliance.86

Anacetrapib is highly protein bound (eg, CETP) in the plasma (.99.5%). It is cleared by oxidative metabolism via Cytochrome P450 3A4 (CYP3A4) with excretion of the metabolites via the biliary/fecal route. Only a trace amount is eliminated by urinary excretion.87 Importantly, while anacetrapib is a sensitive CYP3A4 substrate, anacetrapib neither inhibits nor induces CYP3A4 activity. No meaningful interactions have been found between anacetrapib and simvastatin, digoxin, or warfarin.86 Anacetrapib in part to its redistribution to adipose tissue has a long terminal half-life.88

In terms of safety endpoints, anacetrapib demonstrated no increase in side effects (including myalgia), drug-related adverse effects, adverse events leading to drug discontinuation, or other important safety endpoints, such as BP, electrolyte, aldosterone, creatinine kinase, or transaminase levels. A very small increase in C-reactive protein of undetermined significance was seen with anacetrapib, which notably was also reported with torcetrapib and dalcetrapib in their Phase III studies. It is unknown whether this is a class effect as the small sample size in the evacetrapib Phase II study limits evaluation of small C-reactive protein changes.

It is expected that the REVEAL (the Phase III) population will also have lower starting LDL-C levels, both because statin-intolerant subjects will not be enrolled and because of more stringent lipid entry criteria. The final major difference is that the primary endpoint in REVEAL is focused on coronary events, while ACCELERATE has a broader primary endpoint. A broader primary endpoint along with a slightly higher risk population will allow for a shorter follow-up duration and much smaller sample size in ACCELERATE.

Conclusion

  • CETP remains a valid target and that the lipid changes resulting from its inhibition may be protective. The biology of CETP inhibition is complex, and questions remain regarding which lipid changes (eg, reductions in LDL and Lp(a), increases in HDL) are most likely to be important and whether there are still unknown effects that may negate any overall clinical benefit.
  • if potent CETP inhibition is found to be beneficial, it is still unclear whether this effect will be homogeneous or vary based on individual metabolism.
  • anacetrapib-induced HDL (especially the apoE-rich HDL2 particles) may have an enhanced ability for reverse cholesterol transport without any known adverse effects. Importantly, if a threshold effect for HDL-C augmentation exists, the vast majority of patients taking anacetrapib would be expected to cross it.
  • Despite a difficult beginning for the class of CETP inhibitors, anacetrapib and evacetrapib hold promise as future therapies for patients with atherosclerosis
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52. Bots ML, Visseren FL, Evans GW, et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADI­ANCE 2 study): A randomised, double-blind trial. Lancet. 2007;370(9582):153–160.

53. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007;356(13): 1304–1316.

54. Hu X, Dietz JD, Xia C, et al. Torcetrapib induces aldosterone and cor­tisol production by an intracellular calcium-mediated mechanism inde­pendently of cholesteryl ester transfer protein inhibition. Endocrinology. 2009;150(5):2211–2219.

55. Forrest MJ, Bloomfield D, Briscoe RJ, et al. Torcetrapib-induced blood pressure elevation is independent of CETP inhibition and is accompa­nied by increased circulating levels of aldosterone. Br J Pharmacol. 2008;154(7):1465–1473.

56. DePasquale M, Cadelina G, Knight D, et al. Mechanistic studies of blood pressure in rats treated with a series of cholesteryl ester transfer protein inhibitors. Drug Develop Res. 2009;70(10.1002/ddr.20282):35.

57. Clerc RG, Stauffer A, Weibel F, et al. Mechanisms underlying off-target effects of the cholesteryl ester transfer protein inhibitor torcetrapib involve L-type calcium channels. J Hypertens. 2010;28(8): 1676–1686.

58. Sofat R, Hingorani AD, Smeeth L, et al. Separating the mechanism-based and off-target actions of cholesteryl ester transfer protein inhibitors with CETP gene polymorphisms. Circulation. 2010;121(1): 52–62.

59. Blasi E, Bamberger M, Knight D, et al. Effects of CP-532,623 and torcetrapib, cholesteryl ester transfer protein inhibitors, on arterial blood pressure. J Cardiovasc Pharmacol. 2009;53(6):507–516.

60. Connelly MA, Parry TJ, Giardino EC, et al. Torcetrapib produces endothelial dysfunction independent of cholesteryl ester transfer protein inhibition. J Cardiovasc Pharmacol. 2010;55(5):459–468.

61. Simic B, Hermann M, Shaw SG, et al. Torcetrapib impairs endothelial function in hypertension. Eur Heart J. 2012;33(13):1615–1624.

62. Westerterp M, Koetsveld J, Tall AR. Cholesteryl ester transfer protein inhibition: A dysfunctional endothelium. J Cardiovasc Pharmacol. 2010;55(5):456–458.

63. Guerin M, Le Goff W, Duchene E, et al. Inhibition of CETP by torce­trapib attenuates the atherogenicity of postprandial TG-rich lipoproteins in type IIB hyperlipidemia. Arterioscler Thromb Vasc Biol. 2008;28(1): 148–154.

64. Yvan–Charvet L, Matsuura F, Wang N, et al. Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol. 2007;27(5): 1132–1138.

65. Tall AR. The effects of cholesterol ester transfer protein inhibition on cholesterol efflux. Am J Cardiol. 2009;104(Suppl 10):39E–45E.

66. Tchoua U, D’Souza W, Mukhamedova N, et al. The effect of cholesteryl ester transfer protein overexpression and inhibition on reverse choles­terol transport. Cardiovasc Res. 2008;77(4):732–739.

67. Briand F, Thieblemont Q, Andre A, Ouguerram K, Sulpice T. CETP inhibitor torcetrapib promotes reverse cholesterol transport in obese insulin-resistant CETP-ApoB100 transgenic mice. Clin Transl Sci. 2011;4(6):414–420.

68. Nicholls SJ, Tuzcu EM, Brennan DM, Tardif JC, Nissen SE. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis: Insights from ILLUSTRATE (investigation of lipid level management using coronary ultrasound to assess reduction of atherosclerosis by CETP inhibition and HDL elevation). Circulation. 2008;118(24):2506–2514.

69. Fryirs MA, Barter PJ, Appavoo M, et al. Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion. Arterioscler Thromb Vasc Biol. 2010;30(8):1642–1648.

70. Barter PJ, Rye KA, Tardif JC, et al. Effect of torcetrapib on glucose, insulin, and hemoglobin A1c in subjects in the investigation of lipid level management to understand its impact in atherosclerotic events (ILLUMINATE) trial. Circulation. 2011;124(5):555–562.

71. Funder JW. Aldosterone, hypertension and heart failure: Insights from clinical trials. Hypertens Res. 2010;33(9):872–875.

72. Kuivenhoven JA, de Grooth GJ, Kawamura H, et al. Effectiveness of inhibition of cholesteryl ester transfer protein by JTT-705 in combina­tion with pravastatin in type II dyslipidemia. Am J Cardiol. 2005;95(9): 1085–1088.

73. Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K, Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature. 2000;406(6792):203–207.

74. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, et al. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: A randomized phase II dose-response study. Circulation. 2002;105(18):2159–2165.

75. Niesor EJ, Magg C, Ogawa N, et al. Modulating cholesteryl ester transfer protein activity maintains efficient pre-beta-HDL formation and increases reverse cholesterol transport. J Lipid Res. 2010;51(12): 3443–3454.

76. Derks M, Anzures–Cabrera J, Turnbull L, Phelan M. Safety, tolerability and pharmacokinetics of dalcetrapib following single and multiple ascending doses in healthy subjects: A randomized, double-blind, placebo-controlled, phase I study. Clin Drug Investig. 2011;31(5):325–335.

77. Stein EA, Roth EM, Rhyne JM, Burgess T, Kallend D, Robinson JG. Safety and tolerability of dalcetrapib (RO4607381/JTT-705): Results from a 48-week trial. Eur Heart J. 2010;31(4):480–488.

78. Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalce­trapib on atherosclerotic disease using novel non-invasive multimo­dality imaging (dal-PLAQUE): A randomised clinical trial. Lancet. 2011;378(9802):1547–1559.

79. Luscher TF. Effects of dalcetrapib on vascular function: Results of phase IIb dal-VESSEL study. Available from: http://www.escardio.org/about/press/press-releases/esc11-paris/Pages/HL1-dal-VESSEL.aspx. Updated 2011. Accessed February 1, 2012.

80. Schwartz GG, Olsson AG, Ballantyne CM, et al. Rationale and design of the dal-OUTCOMES trial: Efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J. 2009;158(6):896–901. e3.

81. Miller R. Roche stops dalcetrapib trial for lack of benefit. Available from: http://www.theheart.org/article/1395141.do. Updated 2012. Accessed June 21, 2012.

82. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089–2099.

83. Nicholls SJ, Brewer HB, Kastelein JJ et al. Effects of the CETP Inhibitor evacetrapib administered as monotherpay or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA. 2011;306(19):2099-2109.

84. Eli Lilly and Company. A study of evacetrapib in high-risk vascular disease (ACCELERATE); NCT01687998. Available from: http://www.clinicaltrials.gov/ct2/show/study/NCT01687998?term=evacetrapib&rank=3. Updated 2012. Accessed November 17, 2012.

85. Smith CJ, Ali A, Hammond ML, et al. Biphenyl-substituted oxazolidinones as cholesteryl ester transfer protein inhibitors: Modifica­tions of the oxazolidinone ring leading to the discovery of anacetrapib. J Med Chem. 2011;54(13):4880–4895.

86. Gutstein DE, Krishna R, Johns D, et al. Anacetrapib, a novel CETP inhibitor: Pursuing a new approach to cardiovascular risk reduction. Clin Pharmacol Ther. 2012;91(1):109–122.

87. Kumar S, Tan EY, Hartmann G, et al. Metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in humans. Drug Metab Dispos. 2010;38(3):474–483.

88. Dansky HM, Bloomfield D, Gibbons P, et al. Efficacy and safety after cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib (MK-0859) in patients with primary hypercholesterolemia or mixed hyperlipidemia. Am Heart J. 2011;162(4): 708–716.

89. Bloomfield D, Carlson GL, Sapre A, et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J. 2009;157(2):352–360. e2.

90. Krishna R, Anderson MS, Bergman AJ, et al. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: Two double-blind, randomised placebo-controlled phase I studies. Lancet. 2007;370(9603):1907–1914.

91. Krauss RM, Wojnooski K, Orr J, et al. Changes in lipoprotein subfrac­tion concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib. J Lipid Res. 2012;53(3): 540–547.

92. Krishna R, Bergman AJ, Green M, Dockendorf MF, Wagner JA, Dykstra K. Model-based development of anacetrapib, a novel cholesteryl ester transfer protein inhibitor. AAPS J. 2011;13(2): 179–190.

93. Yvan–Charvet L, Kling J, Pagler T, et al. Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arterioscler Thromb Vasc Biol. 2010;30(7):1430–1438.

94. Castro–Perez J, Briand F, Gagen K, et al. Anacetrapib promotes reverse cholesterol transport and bulk cholesterol excretion in Syrian golden hamsters. J Lipid Res. 2011;52(11):1965–1973.

95. Cannon CP, Dansky HM, Davidson M, et al. Design of the DEFINE trial: Determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib. Am Heart J. 2009;158(4):513–519. e3.

96. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363(25):2406–2415.

97. Davidson M, Liu SX, Barter P, et al. Measurement of LDL-C after treatment with the CETP inhibitor anacetrapib. J Lipid Res. 2013;54(2):467–472.

98. Brinton E, Liu S, Stepanavage M, et al. Lipid-modifying effects of anacetrapib in patients with lower versus higher baseline levels of HDL-C, LDL-C, and TG: Pre-specified subgroup analyses of the DEFINE (determining the efficacy and tolerability of CETP INhibition with AnacEtrapib) trial. Circulation. 2011;124:A9649.

99. Gotto A, Cannon C, Shah S, et al. Lipid modifying effects of anacetrapib: Pre-specified subgroup analyses. Circulation. 2011;124: A15035.

100. Bowman L. REVEAL: Randomized EValuation of the effects of anacetrapib through lipid-modification. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01252953?term=anacetrapib&rank=4. Updated 2011. Accessed June 25, 2012.

101. Cannon CP. High-density lipoprotein cholesterol as the Holy Grail. JAMA. 2011;306(19):2153–2155 Research Reports in Clinical Cardiology 2013:4

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Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients

Curator: Aviva Lev-Ari, PhD, RN

Equation May Give Wrong LDL Status

By Todd Neale, Senior Staff Writer, MedPage Today

Published: March 28, 2013

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

  • The widely used Friedewald equation may be underestimating LDL cholesterol levels in many patients, a study found.
  • Note that 14.6% of the patients in the study were placed into different treatment groups by the Friedewald estimates and direct measurements, mainly due to classification in a lower LDL cholesterol treatment group by Friedewald compared with direct LDL cholesterol.

After excluding the patients who had a triglyceride level of 400 mg/dL or greater — in whom there are known limitations of the Friedewald equation — the researchers examined data from 1,310,440 adults (mean age 59) who underwent lipid screening; 14.6% had a Friedewald-estimated LDL cholesterol level of less than 70 mg/dL, the treatment target for high-risk patients.

“Nevertheless, non-HDL cholesterol and apolipoprotein B are alternative approaches, with potential advantages over any measure of LDL cholesterol, and these measures avoid confusion that arises in defining LDL cholesterol …,” they wrote. “Moreover, in clinical trial patients with LDL cholesterol levels in the high-risk range highlighted in our study, non-HDL cholesterol and apolipoprotein B were stronger markers of residual risk than Friedewald LDL cholesterol.”

Martin S, et al “Friedewald estimated versus directly measured low-density lipoprotein cholesterol and treatment implications” J Am Coll Cardiol 2013; DOI: 10.1016/j.jacc.2013.01.079.

VIEW VIDEOBiomarker Series: Lipoprotein A — WellnessFX

VIEW VIDEO BioMarker Series: Apolipoprotein B — WellnessFX

The widely used Friedewald equation may be underestimating LDL cholesterol levels in many patients, researchers found.

The discrepancy between LDL cholesterol values that were estimated by the Friedewald equation and those that were directly measured was greatest when LDL cholesterol levels were low and triglyceride levels were high, according to Seth Martin, MD, of Johns Hopkins Hospital, and colleagues.

Among patients with a Friedewald-estimated value of less than 70 mg/dL, for example, the directly measured level was a median of 9 mg/dL higher when triglycerides were 150 to 199 mg/dL and 18.4 mg/dL higher when triglycerides were 200 to 399 mg/dL, the researchers reported online in the Journal of the American College of Cardiology.

Overall, 14.6% of the patients included in the study were placed into different treatment groups by the Friedewald estimates and direct measurements. This discordance was mainly due to “classification in a lower LDL cholesterol treatment group by Friedewald compared with direct LDL cholesterol,” which occurred in 11.3% of patients, they noted.

The discordance was greatest “when accuracy is most crucial, in patients with LDL cholesterol levels in the high-risk treatment range and concurrent hypertriglyceridemia,” Martin and colleagues wrote, noting that because the Friedewald estimates were generally lower than the directly measured values, using the equation could result in undertreatment of high-risk patients.

“This phenomenon warrants consideration in contemporary patient care and clinical practice guidelines,” the authors wrote.

With the Friedewald equation, LDL cholesterol is estimated by subtracting the HDL cholesterol level and the triglyceride level (divided by 5) from the total cholesterol level. Using the equation avoids the extra time and expense needed to directly measure LDL with ultracentrifugation.

Since the equation was introduced in 1972, however, practice guidelines have introduced lower LDL cholesterol targets, and high triglyceride levels have become more common due to the increasing problems of obesity, insulin resistance, and diabetes.

To assess the accuracy of the equation in a contemporary setting, the researchers compared Friedewald estimates with direct measurements performed with vertical density gradientultracentrifugation by the Vertical Auto Profile (VAP) from 2009 to 2011.

After excluding the patients who had a triglyceride level of 400 mg/dL or greater — in whom there are known limitations of the Friedewald equation — the researchers examined data from 1,310,440 adults (mean age 59) who underwent lipid screening; 14.6% had a Friedewald-estimated LDL cholesterol level of less than 70 mg/dL, the treatment target for high-risk patients.

The median directly measured LDL cholesterol level was 109 mg/dL. Lipid distributions were similar to those seen in the National Health and Nutrition Examination Survey for 2007 to 2008, indicating that the study sample was nationally representative.

In general, the Friedewald estimates were lower than the direct measurements of LDL cholesterol, and the discordance was greatest among patients with low LDL cholesterol levels and high triglyceride levels.

Of the patients with a Friedewald estimate of less than 70 mg/dL, 23% had a direct measurement that was higher than that. That figure rose to 39% when triglycerides were 150 to 199 mg/dL and 59% when triglycerides were 200 to 399 mg/dL.

The findings could have implications for patient care, according to the researchers.

“While we are not suggesting the need for routine clinical measurement of LDL cholesterol by direct assays, it bears mentioning that multiple direct assays beyond the VAP test [used in this study] are available,” they wrote.

“Nevertheless, non-HDL cholesterol and apolipoprotein B are alternative approaches, with potential advantages over any measure of LDL cholesterol, and these measures avoid confusion that arises in defining LDL cholesterol …,” they wrote. “Moreover, in clinical trial patients with LDL cholesterol levels in the high-risk range highlighted in our study, non-HDL cholesterol and apolipoprotein B were stronger markers of residual risk than Friedewald LDL cholesterol.”

They acknowledged some limitations of the analysis, including the possibility that patients who undergo a VAP test may be a special population and the use of one-time LDL cholesterol measurements. In addition, the researchers did not have access to detailed clinical characteristics of the patients or clinical outcomes or information on statin use and fasting status before the lipid test.

http://www.medpagetoday.com/Cardiology/Dyslipidemia/38147?xid=NL_DHE_2013-03-29

REFERENCES

http://my.americanheart.org/professional/General/Secondary-Prevention-Risk-Reduction-for-Cardiac-and-Vascular-Disease_UCM_432926_Article.jsp

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A Randomized Trial of Bedside Platelet Function Monitoring to Adjust Antiplatelet Therapy Versus Standard of Care in Patients Undergoing Drug Eluting Stent Implantation: The ARCTIC Study
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TRILOGY ACS is an international, phase 3, randomized trial comparing the platelet inhibitor prasugrel+aspirin with clopidogrel+aspirin in medically managed US/NSTEMI ACS patients.

Results of the Trial to Assess Chelation Therapy
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Main Results of the Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) Trial
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LBCT.02     Health Economics and Quality of Life in Contemporary Trials     Sun., Nov. 4, 2012 / 5:30pm-6:43pm

LBCT.03     Treatments for Prevention of Cardiovascular Events: A Population Perspective     Mon., Nov. 5, 2012 /  9:00am-10:28am

LBCT.04     Novel Treatments for Managing Lipid Disorders     Mon., Nov. 5, 2012 / 10:45am-11:55am

LBCT.05     Cell-Based Therapies for Myocardial Regeneration     Tues., Nov. 6, 2012 / 10:45am-12:00pm

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Related articles on this Open Access Online Scientific Journal include the following:

High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk 

Aviva Lev-Ari, PhD, RN, 3/31/2013

Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles

Aviva Lev-Ari, PhD, RN 11/15/2012

Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN, 11/28/2012

What is the role of plasma viscosity in hemostasis and vascular disease risk?

Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN, 11/28/2012

Aviva Lev-Ari, PhD, RN, 3/7/2013

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Curator: Aviva Lev-Ari, PhD, RN

If Biologics will help increase HDL in wide market penetration, the market share of Statins will be negatively impacted.

The biologics was developed by NIH funding, as reported on 2/14/2012, see last section, below.

NHLBI SMARTT Program Awards AlphaCore Pharma Funding to Manufacture Potential Treatment for Familial Lecithin-Cholesterol Acyltransferase (LCAT) Deficiency

 

In an Interview I had with the VP of Scientific Affairs at AstraZenaca on 3/18/2013, the Executive Dr. D.S., MD, PhD, told me that the Cardiovascular Therapeutic Area at AstraZeneca is at present and in the future, probably the most important one of all of its businesses to date, thus, the position he is interviewing for, Director of Scientific Affairs Cardiovascular, will be the most powerful one within the Scientific Affairs Office.

Per my discussion of BRILINTA (ticagrelor), referring the VP to my post on this topic on 12/28/2012,

PLATO Trial on ACS: BRILINTA (ticagrelor) better than Plavix® (clopidogrel bisulfate): Lowering chances of having another heart attack

VP said, “the position will be beyond BRILINTA, or Cardiovascular.” A candidate not found yet. AZ keeps on calling, Keeps searching.

AstraZeneca – The Biggest R&D Spenders In Biopharma

Company: AstraZeneca

2011 spending: $5.5 billion
2010 spending: $5.3 billion
Change: +3.6%
Percentage of revenue: 16.3%

Like several other top 10 pharma companies, AstraZeneca ($AZN) saw its R&D expenses climb somewhat in 2011. But this year, as CEO David Brennan unveiled the annual results for 2011, he started with a new restructuring plan. And R&D is intended to bear some of the biggest cuts.

Hit with sliding profits and eviscerated by analysts for one of the weakest late-stage pipelines in the Big Pharma business, Brennan had to do something significant. Of more than 7,000 pink slips being readied, 2,200 were being reserved for R&D as the company moved to shutter R&D facilities in Soedertaelje in Sweden and Montreal. Neuroscience, once a key feature in the pipeline, is being scaled way back, with plans to field a “virtual” team in key hubs.

AstraZeneca became the poster child for the R&D quagmire when Forbes‘ Matthew Herper concluded that AstraZeneca had the worst ratio of R&D costs to approvals in the industry. For a company that went 6 years without a drug approval ahead of the 2009 OK for Onglyza, accumulated setbacks have reached a breaking point.

AstraZeneca, though, can’t cut its way to a turnaround in R&D. That’s going to take new programs and new technologies. It only began to address the issue with a licensing pact for a slate of Amgen antibodies. Research chief Martin Mackay was quick to follow up by telling Reuters‘ Ben Hirschler that more deals were coming. And indeed just weeks later, AstraZeneca acquired a late-stage gout drug with the $1.26 billion buyout of Ardea. The fact that AstraZeneca didn’t bother to stick with its disease strategy, and quickly indicated that it wouldn’t in the future, underscored just how crucial it is to move fast.

Nevertheless, AstraZeneca will find it hard to shake its legacy of failures. Just weeks ago the company was forced to wash its hands of a billion-dollar deal with Targacept ($TRGT) for a prospective depression drug that failed 4 out of 4 late-stage studies. And as criticism mounted, Brennan has been forced to adopt a defensive posture.

“I read and hear and see lots of things, but we’re here trying to change policy, make good decisions and execute our strategy,” the CEO told Bloomberg, vowing to stick to the game plan. “Maybe somebody sees something different, but spending more money does not have a linear increase in the number of returns you get from a research and development perspective.”

AstraZeneca – The Biggest R&D Spenders In Biopharma – FierceBiotech http://www.fiercebiotech.com/special-reports/biggest-rd-spenders-biopharma/astrazeneca-biggest-rd-spenders-biopharma#ixzz2PQN8is2U

On April 3, 2013, FierceBiotech reported that

MEDIMMUNE, ASTRAZENECA’S BIOLOGICS ARM, ACQUIRES ALPHACORE PHARMA

3 April 2013

AstraZeneca today announced that MedImmune, its global biologics research and development arm, has acquired AlphaCore Pharma, an Ann Arbor, Michigan-based biotechnology company focused on the development of ACP-501, a recombinant human lecithin-cholesterol acyltransferase (LCAT) enzyme.

LCAT, an enzyme in the bloodstream, is a key component in the reverse cholesterol transport (RCT) system, which is thought to play a major role in driving the removal of cholesterol from the body and may be critical in the management of high-density lipoprotein (HDL) cholesterol levels.  The LCAT enzyme could also play a role in a rare, hereditary disorder called familial LCAT deficiency (FLD) in which the LCAT enzyme is absent.

Cardiovascular and metabolic disease is a core therapy area for AstraZeneca’s small and large molecule research.

“As the science in this area continues to evolve, we are committed to exploring unique pathways that could lead to new combination or standalone therapies for patients living with chronic and acute cardiovascular diseases,” said Dr. Bahija Jallal, Executive Vice President, MedImmune. “Cardiovascular disease is projected to remain the single leading cause of death worldwide over the next decade and beyond. Through novel approaches like LCAT, we hope to shift the treatment paradigms in this area to help prevent and treat these conditions.”

In 2012, results from a Phase I clinical trial of ACP-501 met the primary safety and tolerability endpoints.  No serious adverse events were reported.  ACP-501 also met the study’s secondary endpoints by rapidly and substantially elevating HDL cholesterol.  The data from this study support ongoing clinical development of ACP-501.

MEDIMMUNE, ASTRAZENECA’S BIOLOGICS ARM, ACQUIRES ALPHACORE PHARMA – FierceBiotech http://www.fiercebiotech.com/press-releases/medimmune-astrazenecas-biologics-arm-acquires-alphacore-pharma#ixzz2PQL73X3f

 AstraZeneca gambles on cardio therapy in AlphaCore buyout

By Ryan McBride

In another early-stage bet, AstraZeneca’s MedImmune unit acquired the biotech AlphaCore Pharma. The deal comes as AstraZeneca ($AZN) reboots a floundering R&D effort and adds a recombinant LCAT enzyme therapy from AlphaCore that could combat cardiovascular disease.

MedImmune, the biologics division of Astra, faces years of additional development before AlphaCore’s ACP-501 becomes part of the London-based pharma group’s late-stage pipeline, which has many holes yet to be filled. Last year, Ann Arbor, MI-based AlphaCore touted Phase I work on ACP-501, reporting that the enzyme therapy was well-tolerated and quickly boosted levels of HDL or “good” cholesterol in patients.

AZ CEO Pascal Soriot

New AstraZeneca CEO Pascal Soriot has signaled his desire to wager on new science amid an overhaul of R&D announced last month that will cost 1,600 research jobs across the company and after the ouster of former R&D chief Martin Mackay in January. Bahija Jallal, executive vice president of MedImmune, survived the round of cutbacks and plans to pursue new biologics such as ACP-501, which she stated could treat both acute and chronic cardiovascular disease.

“Cardiovascular disease is projected to remain the single leading cause of death worldwide over the next decade and beyond,” Jallal said. “Through novel approaches like LCAT, we hope to shift the treatment paradigms in this area to help prevent and treat these conditions.”

The ACP-501 is an engineered version of the natural LCAT enzyme from the liver that plays a role in ridding the body of cholesterol and keeping up levels of beneficial HDL cholesterol. The candidate could aid millions of patients with cholesterol problems as well as those with a rare inherited disease called familial LCAT deficiency that robs the body of the enzyme.

Bahija Jallal, EVP of MedImmune

The AlphaCore buyout comes on the heels of AstraZeneca’s sizable $240 million upfront payment to Moderna Therapeutics to get in early on the startup’s preclinical programs that use messenger RNA to turn cells in the body into makers of healing proteins. The financial details of the AlphaCore buyout weren’t disclosed.

Still, analysts expect Soriot to pull the trigger on larger deals to bolster the late-stage pipeline or even provide marketed products as AstraZeneca faces the impact of patent expirations on blockbuster cholesterol pill Crestor and the heartburn med Nexium. As Reuters noted, the company has only 6 drugs in late-stage development and aims to double that number by 2016.

 SOURCE:
February 14, 2012 09:17 AM Eastern Daylight Time

NHLBI SMARTT Program Awards AlphaCore Pharma Funding to Manufacture Potential Treatment for Familial Lecithin-Cholesterol Acyltransferase (LCAT) Deficiency

ANN ARBOR, Mich. & ROCKVILLE, Md.–(BUSINESS WIRE)–AlphaCore Pharma, a biopharmaceutical company, and Advanced Bioscience Laboratories (ABL), a biomedical contract research and manufacturing company, today announce funding from the National Institutes of Health, National Heart, Lung and Blood Institute (NHLBI) “Science Moving towards Research Translation and Therapy” (SMARTT) program, to manufacture recombinant human lecithin-cholesterol acyltransferase (rhLCAT) for the treatment of familial LCAT deficiency.

“This is a significant step towards developing a treatment for familial LCAT deficiency. We are pleased by the strong support from the NHLBI and ABL and look forward to advancing this program.”

Also known as ACP-501, rhLCAT represents a promising new approach in the fight against atherosclerotic cardiovascular disease, and has demonstrated preclinical efficacy in promoting HDL maturation and cholesterol flux, a natural process by which cholesterol is removed from the body. Currently, ACP-501 is in Phase 1 clinical development with the eventual goal of reducing the risk of cardiovascular events in patients presenting with acute coronary syndrome. Manufacturing support from the NHLBI SMARTT program will enable production of additional material that will be used to determine the safety and efficacy of rhLCAT enzyme replacement therapy for patients with familial LCAT deficiency – a potentially life-threatening illness for which there is no FDA-approved treatment.

“This is a significant step towards developing a treatment for familial LCAT deficiency. We are pleased by the strong support from the NHLBI and ABL and look forward to advancing this program.” said AlphaCore President, Bruce Auerbach.

The enzyme, rhLCAT, will be produced by ABL in its Rockville, MD biologics production facility under a contract from the NHLBI SMARTT program. Dr. Thomas VanCott, ABL’s President and Chief Executive Officer stated, “ABL is privileged to be working with AlphaCore Pharma in support of their ACP-501 (rhLCAT) program. Research in rare genetic diseases can encounter funding hurdles, yet through this NHLBI-sponsored manufacturing project we have the potential to advance an urgently needed enzyme replacement therapy. This effort further demonstrates ABL’s expertise of partnering with the NIH to support major development programs and our commitment to deliver the highest quality cGMP biologics to our clients in a cost-effective manner.”


Peter Greenleaf, chief executive of MedImmune. (Jeffrey MacMillan – JEFFREY MACMILLAN)Peter Greenleaf is stepping down down as president of Gaithersburg-based biotechnology giant MedImmune, according to a company spokesman, to take the helm of parent company AstraZeneca’s Latin America business.

He will be replaced by Bahija Jallal, who currently serves as MedImmune’s executive vice president of research and development. Jallal joined the company in 2006 as vice president of translational sciences.

The leadership change comes as MedImmune was formally designated a biologics research and development site for AstraZeneca, meaning Jallal will report directly to AstraZeneca chief executive Pascal Soriot, said company spokesman Mike O’Brien.

He added that MedImmune’s commercial organization will now report into AstraZeneca’s North American business and its manufacturing group will be folded into AstraZeneca’s global operations group.

“There’s no new news on jobs today,” O’Brien said. “The driver for these changes is not cost but even faster decision-making in key areas of the business and a need to reduce complexity.”

O’Brien said Greenleaf will continue to be based in Maryland, where he has become a figure­head of sorts for the life sciences industry.

Greenleaf was an advocate for Democratic Gov. Martin O’Malley’s InvestMaryland initiative, which allocates state money for investment in local upstarts. He serves as chairman of the Maryland Venture Fund Authority, a nine-member board assigned to oversee its implementation.

MedImmune has long been an anchor of Maryland’s biotechnology hub along the Interstate 270 corridor. The company was purchased by AstraZeneca in 2007 for $15.6 billion, a sales price that some industry observers still question.

The Washington Business Journal reported the personnel changes earlier.

 SOURCE:

REFERENCES

Mineo C, Yuhanna IS, Quon MJ, Shaul PW., (2003). HDL-induced eNOS activation is mediated by Akt and MAP kinases. J. Biol. Chem., 278:9142–9149.

Shaul, PW and Mineo, C, (2004). HDL action on the vascular wall: is the answer NO? J Clin Invest., 15; 113(4): 509–513.

Other related articles to this topic on the Open Access Online Scientific Journal include the following:

Aviva Lev-Ari, PhD, RN, 4/7/2013

 

Read Full Post »


Curator: Aviva Lev-Ari, PhD, RN

Evidence of HDL Modulation of eNOS in Humans

 Whereas the functional link between HDL and eNOS has been appreciated only recently, the relationship between HDL and endothelium-dependent vasodilation has been known for some time. In studies of coronary vasomotor responses to acetylcholine, it was noted in 1994 that patients with elevated HDL have greater vasodilator and attenuated vasoconstrictor responses (Zeiher et al., 1994).

Circulation, 89:2525–2532.

Studies of flow-mediated vasodilation of the brachial artery have also shown that HDL cholesterol is an independent predictor of endothelial function (Li et al., 2000).

Int. J. Cardiol., 73:231–236

Induction of NO Production and Stimulation of eNOS

Mechanism of Action (MOA) for Nitric Oxide (NO) and endothelial Nitric Oxide Syntase (eNOS) are described in George T. and P. Ramwell, (2004). Nitric Oxide, Donors, & Inhibitors. Chapter 19 in Katzung, BG., Basic & Clinical Pharmacology. McGraw-Hill, 9th Edition, pp. 313 – 318

http://books.google.com/books/about/Basic_and_Clinical_Pharmacology.html?id=4O7ghcthkt4C

The direct, short-term impact of HDL on endothelial function also has recently been investigated in humans. One particularly elegant study recently evaluated forearm blood flow responses in individuals who are heterozygous for a loss-of-function mutation in the ATP-binding cassette transporter 1 (ABCA1) gene. Compared with controls, ABCA1 heterozygotes (six men and three women) had HDL levels that were decreased by 60%, their blood flow responses to endothelium-dependent vasodilators were blunted, and endothelium-independent responses were unaltered. After a 4-hour infusion of apoAI/phosphatidylcholine disks, their HDL level increased threefold and endothelium-dependent vasomotor responses were fully restored (Bisoendial et al., 2003). It has also been observed that endothelial function is normalized in hypercholesterolemic men with normal HDL levels shortly following the administration of apoAI/phosphatidylcholine particles (Spieker et al., 2002).

Circulation, 105:1399–1402.

Thus, evidence is now accumulating that HDL is a robust positive modulator of endothelial NO production in humans (Shaul & Mineo, 2004).

J Clin Invest., 15; 113(4): 509–513.

HDL is more than an eNOS Agonist

 In addition to the modulation of NO production by signaling events that rapidly dictate the level of enzymatic activity, important control of eNOS involves changes in the abundance of the enzyme. In a clinical trial by the Karas laboratory of niacin therapy in patients with low HDL levels (nine males and two females), flow-mediated dilation of the brachial artery was improved in association with a rise in HDL of 33% over 3 months (Kuvin et al., 2002).

Am. Heart J., 144:165–172.

They also demonstrated that eNOS expression in cultured human endothelial cells is increased by HDL exposure for 24 hours. They further showed that the increase in eNOS is related to an increase in the half-life of the protein, and that this is mediated by PI3K–Akt kinase and MAPK (Ramet et al., 2003).

J. Am. Coll. Cardiol., 41:2288–2297.

Thus, the same mechanisms that underlie the acute activation of eNOS by HDL appear to be operative in upregulating the expression of the enzyme.

The current understanding of the mechanism by which HDL enhances endothelial NO production is summarized in Shaul & Mineo (2004), Figure 1.

J Clin Invest., 15; 113(4): 509–513.

It describes the mechanism of action for HDL enhancement of NO production by eNOS in vascular endothelium.

(a)   HDL causes membrane-initiated signaling, which stimulates eNOS activity. The eNOS protein is localized in cholesterol-enriched (orange circles) plasma membrane caveolae as a result of the myristoylation and palmitoylation of the protein. Binding of HDL to SR-BI via apoAI causes rapid activation of the nonreceptor tyrosine kinase src, leading to PI3K activation and downstream activation of Akt kinase and MAPK. Akt enhances eNOS activity by phosphorylation, and independent MAPK-mediated processes are additionally required (Duarte, et al., 1997). .Eur J Pharmacol, 338:25–33. HDL also causes an increase in intracellular Ca2+ concentration (intracellular Ca2+ store shown in blue; Ca2+ channel shown in pink), which enhances binding of calmodulin (CM) to eNOS. HDL-induced signaling is mediated at least partially by the HDL-associated lysophospholipids SPC, S1P, and LSF acting through the G protein–coupled lysophospholipid receptor S1P3. HDL-associated estradiol (E2) may also activate signaling by binding to plasma membrane–associated estrogen receptors (ERs), which are also G protein coupled. It remains to be determined if signaling events are also directly mediated by SR-BI (Yuhanna et al., 2001), (Nofer et al., 2004), (Gong et al., 2003), (Mineo et al., 2003).

Nat. Med.7:853–857.

J. Clin. Invest.,113:569–581.

J. Clin. Invest., 111:1579–1587.

J. Biol. Chem., 278:9142–9149.

(b)   HDL regulates eNOS abundance and subcellular distribution. In addition to modulating the acute response, the activation of the PI3K–Akt kinase pathway and MAPK by HDL upregulates eNOS expression (open arrows). HDL also regulates the lipid environment in caveolae (dashed arrows). Oxidized LDL (OxLDL) can serve as a cholesterol acceptor (orange circles), thereby disrupting caveolae and eNOS function. However, in the presence of OxLDL, HDL maintains the total cholesterol content of caveolae by the provision of cholesterol ester (blue circles), resulting in preservation of the eNOS signaling module (Ramet et al., 2003), (Blair et al., 1999), (Uittenbogaard et al., 2000).

J. Am. Coll. Cardiol., 41:2288–2297.

J. Biol. Chem., 274:32512–32519.

J. Biol. Chem., 275:11278–11283.

Source for HDL-eNOS Figure: Shaul & Mineo (2004).

 

HDL enhances NO production by eNOS in vascular endothelium.

FIGURE SOURCE:

Shaul, PW and Mineo, C, (2004). HDL action on the vascular wall: is the answer NO? J Clin Invest., 15; 113(4): 509–513.

eNOS is not Activated by Nebivolol in Human Failing Myocardium.

Nebivolol is a highly selective beta(1)-adrenoceptor blocker with additional vasodilatory properties, which may be due to an endothelial-dependent beta(3)-adrenergic activation of the endothelial nitric oxide synthase (eNOS). beta(3)-adrenergic eNOS activation has been described in human myocardium and is increased in human heart failure. Therefore, this study investigated whether nebivolol may induce an eNOS activation in cardiac tissue. Immunohistochemical stainings were performed using specific antibodies against eNOS translocation and eNOS serine(1177) phosphorylation in rat isolated cardiomyocytes, human right atrial tissue (coronary bypass-operation), left ventricular non-failing (donor hearts) and failing myocardium after application of the beta-adrenoceptor blockers nebivolol, metoprolol and carvedilol, as well as after application of BRL 37344, a specific beta(3)-adrenoceptor agonist. BRL 37344 (10 muM) significantly increased eNOS activity in all investigated tissues (either via translocation or phosphorylation or both). None of the beta-blockers (each 10 muM), including nebivolol, increased either translocation or phosphorylation in any of the investigated tissues. In human failing myocardium, nebivolol (10 muM) decreased eNOS activity. In conclusion, nebivolol shows a tissue-specific eNOS activation. Nebivolol does not activate the endothelial eNOS in end-stage human heart failure and may thus reduce inhibitory effects of NO on myocardial contractility and on oxidative stress formation. This mode of action may be of advantage when treating heart failure patients.

Brixius K, Song Q, Malick A, Boelck B, Addicks K, Bloch W, Mehlhorn U, Schwinger R, (2006). eNOS is not activated by nebivolol in human failing myocardium.

Life Sci. 2006 Apr 25

REFERENCES

Brixius K, Song Q, Malick A, Boelck B, Addicks K, Bloch W, Mehlhorn U, Schwinger R, (2006). eNOS is not activated by nebivolol in human failing myocardium.

Life Sci. 2006 Apr 25

Mineo C, Yuhanna IS, Quon MJ, Shaul PW., (2003). HDL-induced eNOS activation is mediated by Akt and MAP kinases. J. Biol. Chem., 278:9142–9149.

Shaul, PW and Mineo, C, (2004). HDL action on the vascular wall: is the answer NO? J Clin Invest., 15; 113(4): 509–513.

Read Full Post »


Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles

Reporter: Aviva Lev-Ari, PhD, RN

Updated 3/5/2013

Genetic Associations with Valvular Calcification and Aortic Stenosis

N Engl J Med 2013; 368:503-512

February 7, 2013DOI: 10.1056/NEJMoa1109034

METHODS

We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.

CONCLUSIONS

Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)

SOURCE:

N Engl J Med 2013; 368:503-512

HDL is more than an eNOS Agonist

 In addition to the modulation of NO production by signaling events that rapidly dictate the level of enzymatic activity, important control of eNOS involves changes in the abundance of the enzyme. In a clinical trial by the Karas laboratory of niacin therapy in patients with low HDL levels (nine males and two females), flow-mediated dilation of the brachial artery was improved in association with a rise in HDL of 33% over 3 months (Kuvin et al., 2002).

Am. Heart J., 144:165–172.

They also demonstrated that eNOS expression in cultured human endothelial cells is increased by HDL exposure for 24 hours. They further showed that the increase in eNOS is related to an increase in the half-life of the protein, and that this is mediated by PI3K–Akt kinase and MAPK (Ramet et al., 2003).

J. Am. Coll. Cardiol., 41:2288–2297.

Thus, the same mechanisms that underlie the acute activation of eNOS by HDL appear to be operative in upregulating the expression of the enzyme.

The current understanding of the mechanism by which HDL enhances endothelial NO production is summarized in Shaul & Mineo (2004), Figure 1.

J Clin Invest., 15; 113(4): 509–513.

It describes the mechanism of action for HDL enhancement of NO production by eNOS in vascular endothelium.

(a)   HDL causes membrane-initiated signaling, which stimulates eNOS activity. The eNOS protein is localized in cholesterol-enriched (orange circles) plasma membrane caveolae as a result of the myristoylation and palmitoylation of the protein. Binding of HDL to SR-BI via apoAI causes rapid activation of the nonreceptor tyrosine kinase src, leading to PI3K activation and downstream activation of Akt kinase and MAPK. Akt enhances eNOS activity by phosphorylation, and independent MAPK-mediated processes are additionally required (Duarte, et al., 1997). Eur J Pharmacol, 338:25–33.

HDL also causes an increase in intracellular Ca2+ concentration (intracellular Ca2+ store shown in blue; Ca2+ channel shown in pink), which enhances binding of calmodulin (CM) to eNOS. HDL-induced signaling is mediated at least partially by the HDL-associated lysophospholipids SPC, S1P, and LSF acting through the G protein–coupled lysophospholipid receptor S1P3. HDL-associated estradiol (E2) may also activate signaling by binding to plasma membrane–associated estrogen receptors (ERs), which are also G protein coupled. It remains to be determined if signaling events are also directly mediated by SR-BI (Yuhanna et al., 2001), (Nofer et al., 2004), (Gong et al., 2003), (Mineo et al., 2003).

Nat. Med., 7:853–857.

J. Clin. Invest.,113:569–581.

J. Clin. Invest., 111:1579–1587.

J. Biol. Chem., 278:9142–9149.

(b)   HDL regulates eNOS abundance and subcellular distribution. In addition to modulating the acute response, the activation of the PI3K–Akt kinase pathway and MAPK by HDL upregulates eNOS expression (open arrows). HDL also regulates the lipid environment in caveolae (dashed arrows). Oxidized LDL (OxLDL) can serve as a cholesterol acceptor (orange circles), thereby disrupting caveolae and eNOS function. However, in the presence of OxLDL, HDL maintains the total cholesterol content of caveolae by the provision of cholesterol ester (blue circles), resulting in preservation of the eNOS signaling module (Ramet et al., 2003), (Blair et al., 1999), (Uittenbogaard et al., 2000).

J. Am. Coll. Cardiol., 41:2288–2297.

J. Biol. Chem., 274:32512–32519.

J. Biol. Chem., 275:11278–11283.

SOURCE:

Shaul, PW and Mineo, C, (2004). HDL action on the vascular wall: is the answer NO? J Clin Invest., 15; 113(4): 509–513.

Are Additional Lipid Measures Useful?

Ryan D. Bradley, ND; and Erica B. Oberg, ND, MPH

http://www.imjournal.com/resources/web_pdfs/recent/1208_bradley.pdf

Total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) are the well-established standards by which clinicians identify individuals at risk for coronary artery disease (CAD), yet nearly 50% of people who have a myocardial infarction have normal cholesterol levels. Measurement of additional biomarkers may be useful to more fully stratify patients according to disease risk. The typical lipid panel includes TC, LDL-C, high-density lipoprotein cholesterol  (HDL-C), and triglycerides (TGs). Emerging biomarkers for cardiovascular risk include measures of LDL-C pattern, size,  and density; LDL particle number; lipoprotein(a); apolipoproteins  (apoA1 and apoB100 being the most useful);  C-reactive protein; and lipoprotein-associated phospholipase

Some of these emerging biomarkers have been proven to add to, or be more accurate than, traditional risk factors in predicting coronary artery disease and, thus, may be useful for clinical decision-making in high-risk patients and in patients with borderline traditional risk factors.  However, we still believe that until treatment strategies can uniquely address these added risk factors—ie, until protocols to rectify unhealthy findings are shown to improve cardiovascular outcomes—healthcare providers should continue to focus primarily on helping patients reach optimal LDL-C, HDL-C, and TG levels

Table 1. Traditional Lipid Panel and Recommended Treatment

Goals for Cardiovascular Disease Prevention34

  • Total Cholesterol Desirable (low) < 200 mg/dL
  • Borderline high 200-239 mg/dL
  • High 240 mg/dL or greater
  • HDL Cholesterol Desirable (high) > 60 mg/dL
  • Acceptable 40-60 mg/dL
  • Low < 40 mg/dL
  • LDL Cholesterol Desirable (low) < 100 mg/dL
  • Acceptable 100-129 mg/dL
  • Borderline high 130-159 mg/dL
  • High 160-189 mg/dL
  • Very high 190 mg/dL or greater
  • Triglycerides Desirable (low) < 150 mg/dL
  • Borderline high 150-199 mg/dL
  • High 200-499 mg/dL
  • Very high 500 mg/dL or greater

LDL-C and HDL-C: Pattern, Size, and Density

Two patterns predominate and are used to describe the average size of LDL particles. Pattern A refers to a preponderance of large LDL particles, while Pattern B refers to a preponderance of small LDL particles; a minority of individuals displays an intermediate or mixed pattern. Some commercially available assays further subdivide LDL-C into 7 distinct designations based on particle size.9,10

LDL Lipoprotein Particle Number

LDL particle number (LDL-P) is a measure of the number of lipoprotein particles independent of the quantity of lipid within the cholesterol particle; ie, LDL-P measures the number of individual particles, not a concentration like LDL-C. It is measured using nuclear magnetic resonance technology and is unaffected by fasting status.21 Higher LDL-P measures have been associated with a higher risk of CAD. This might simply be because there are more particles susceptible to oxidation in circulation.

There are suggestions, but not definitive proof, that reducing LDL-P increases intra-LDL antioxidant capacity.  The European Prospective Investigation of Cancer (EPIC)-Norfolk cohort, a study that has followed 25 663 participants  (men and women aged 45-79 years) over 6 years, evaluated associations between LDL-P and risk of CAD. Compared to controls,  cases of CAD had a higher number of LDL particles (LDL-P P<.0001), smaller average LDL-particle size (P=.002), and higher concentrations of small LDL particles (P<.0001).22

Once again,  small, dense LDL-C were positively associated with TG and negatively associated with HDL.  In another study investigating incident angina and MI with LDL-P, females, but not males, had a significantly increased odds ratio for incident MI and angina for higher LDL-P—but not for LDL size—after adjustment for LDL, age, and race.  Males had increased (but not significant) point estimates showing the same relationship.23 Of note, LDL-P and non-HDL-C (ie,  TC minus HDL-C, or, specifically, LDL-C plus VLDLs), added equivalently to Framingham-predicted CAD risk stratification, thus reducing our enthusiasm for this additional measurement when TC and HDL-C are routinely available.22 Based on these results, LDL-P is becoming recognized as a more-precise measure of LDL-related risk and, as it becomes more available, is likely to replace LDL-C in risk-stratification tools. Clinical availability is currently limited; however, Medicare recently began reimbursing for regular testing of LDL-P in highrisk patients, so we should see availability increase soon. There are no novel treatments based on LDL-P at this time, and data shows therapies that lower LDL-C lower LDL-P as well.

 Apolipoproteins

Apolipoproteins are the protein components of plasma lipoproteins. Several different apolipoproteins have been identified and numbered; however, apoB48, apoB100, and apoA are the most commonly referenced.  ApoB48 is associated with LDL particles that transport dietary cholesterol to the liver for processing. ApoB100 is found in lipoproteins originating from the liver (eg, LDL and VLDL); it transports these lipoproteins and, also, TGs to the periphery. In addition, ApoB100 is involved with the binding of LDL particles to the vascular wall, implicating itself as a key player in the development of atherogenic plaques. Importantly, there is one apoB100 molecule per hepatic-derived lipoprotein. Hence, it is possible to quantify the number of LDL/VLDL particles by noting the total apoB100 concentration.

Measurement of apoB100 has been shown in nearly all studies to outperform LDL-C and non-HDL-C as a predictor of CAD events and as an index of residual CAD risk, perhaps due to differences in measurement sensitivity between measurement methodologies. Direct measurement of apolipoproteins is superior to calculated lipid measurements. Yet, currently, apoB100 measurement is more costly than routine measurements and,  because apoB100 is so closely associated with non-HDL-C (which,  as mentioned previously, can be estimated by TC minus HDL-C),  our enthusiasm for the clinical use of this test is limited.24 For its part, apoA is associated with HDL particles; the 2 major proteins in HDL are apoAI and apoAII. Of these, apoAI has more frequently been used to estimate HDL-C, but, in contrast to apoB100, apoAI is not unique to HDL and so the ratio of apoAI to HDL is not 1 to 1.24

Lipoprotein(a)

Lipoprotein(a)—Lp(a)—is attached to apoB. The association of Lp(a) with CAD and its ability to act as a biomarker of risk appears to be strongest in patients with hypercholesterolemia and, in particular, in young patients with premature atherosclerosis (males younger than 55 and females younger than 65). Part of the reason for this is the observation that there seem to be important threshold effects such that only very high Lp(a) levels (> 30 mg/dL) are associated with elevated vascular risk; in this regard, these increased plasma levels of Lp(a) independently predict the presence of CAD, particularly in patients with elevated LDL-C levels.28

In the Cardiovascular Health Study, a relative risk of approximately 3-fold for death from vascular events and stroke was seen in the highest quintile compared to the lowest quintile of Lp(a) but for males only, whereas no such relation existed for women.29 Lp(a) is commonly considered a marker for familial hypercholesterolemia. Lp(a) may best be used in assessing the risk of younger males with strong family histories of CVD but  should not be used more generally.

Risk Factors for Cardiovascular Disease

(Exclusive of LDL Cholesterol)34

  • Cigarette smoking
  • Hypertension (BP > 140/90 mmHg or on antihypertensive medication)
  • Low HDL cholesterol (< 40 mg/dL)
  • Family history of premature CHD (CHD in first-degree male relative <
  • 55 years; CHD in first-degree female relative < 65 years)
  • Age (men > 44 years; women > 54 years

In addition,

  • Clinical coronary heart disease,
  • symptomatic carotid artery disease,
  • peripheral arterial disease, or
  • abdominal aortic aneurysm

Conclusion

In the United States, treatment guidelines for high CVD risk factors are set by the National Cholesterol Education Program (NCEP) Expert Panel, which developed the third report of the Adult Treatment Panel (ATPIII).34 Treatment goals are determined according to risk stratification by LDL-C and by known additional risk factors such as smoking, low HDL, hypertension,  family history, and age. Yet, clinically, decision-making is always more complex than this. Additional risk stratification can be accomplished by measuring the biomarkers discussed above, and this may potentially provide additive benefit beyond NCEP guidelines. However, we always encourage clinicians to treat known risks to goal levels before adding additional goals for treatment. In a future article we will provide further detail on treatment options for novel biomarkers.

REFERENCES

1. No authors listed. Cardiovascular disease statistics. American Heart Association.

Available at: http://www.americanheart.org/presenter.jhtml?identifier=4478.

Accessed October 28, 2008.

2. Tsimikas S, Willerson JT, Ridker PM. C-reactive protein and other emerging blood

biomarkers to optimize risk stratification of vulnerable patients. J Am Coll Cardiol.

2006;47(8 Suppl):C19-C31.

3. Nicholls SJ, Tuzcu EM, Sipahi I, et al. Statins, high-density lipoprotein cholesterol,

and regression of coronary atherosclerosis. JAMA. 2007;297(5):499-508.

4. Hausenloy DJ, Yellon DM. Targeting residual cardiovascular risk: raising high-density

lipoprotein cholesterol levels. JAMA. 2007;297(5):499-508.

5. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with

nonfasting triglycerides and risk of cardiovascular events in women. JAMA.

2007;298(3):309-316.

6. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides

and risk of myocardial infarction, ischemic heart disease, and death in men and

women. JAMA. 2007;298(3):299-308.

7. Stampfer MJ, Krauss RM, Ma J, et al. A prospective study of triglyceride level, lowdensity

lipoprotein particle diameter, and risk of myocardial infarction. JAMA.

1996;276(11):882-888.

8. Ceriello A. The post-prandial state and cardiovascular disease: relevance to diabetes

mellitus. Diabetes Metab Res Rev. 2000;16(2):125-132.

9. Carmena R, Duriez P, Fruchart JC. Atherogenic lipoprotein particles in artherosclerosis.

Circulation. 2004;109(23 Suppl 1):III2-III7.

10. Dormans TP, Swinkels DW, de Graaf J, Hendriks JC, Stalenhoef AF, Demacker PN.

Single-spin density-gradient ultracentrifugation vs gradient gel electrophoresis: two

methods for detecting low-density-lipoprotein heterogeneity compared. Clin Chem.

1991;37(6):853-858.

11. Roheim PS, Asztalos BF. Clinical significance of lipoprotein size and risk for coronary

atherosclerosis. Clin Chem. 1995;41(1):147-152.

12. Swinkels DW, Demacker PN, Hendriks JC, van ‘t Laar A. Low density lipoprotein

subfractions and relationship to other risk factors for coronary artery disease in

healthy individuals. Arteriosclerosis. 1989;9(5):604-613.

13. Tan CE, Chew LS, Chio LF, et al. Cardiovascular risk factors and LDL subfraction

profile in Type 2 diabetes mellitus subjects with good glycaemic control. Diabetes Res

Clin Pract. 2001;51(2):107-114.

14. Lamarche B, Tchernof A, Mauriège P, et al. Fasting insulin and apolipoprotein B levels

and low-density lipoprotein particle size as risk factors for ischemic heart disease.

JAMA. 1998;279(24):1955-1961.

15. St-Pierre AC, Ruel IL, Cantin B, et al. Comparison of various electrophoretic characteristics

of LDL particles and their relationship to the risk of ischemic heart disease.

Circulation. 2001;104(19):2295-2299.

16. Mora S, Szklo M, Otvos JD, et al. LDL particle subclasses, LDL particle size, and

carotid atherosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA).

Atherosclerosis. 2007;192(1):211-217.

17. Singh IM, Shishehbor MH, Ansell BJ. High-density lipoprotein as a therapeutic target:

a systematic review. JAMA. 2007;298(7):786-798.

18. Lewis GF. Determinants of plasma HDL concentrations and reverse cholesterol

transport. Curr Opin Cardiol. 2006;21(4):345-352.

19. Kontush A, de Faria EC, Chantepie S, Chapman MJ. A normotriglyceridemic, low

HDL-cholesterol phenotype is characterised by elevated oxidative stress and HDL

particles with attenuated antioxidative activity. Atherosclerosis. 2005;182(2):277-285.

20. Nobécourt E, Jacqueminet S, Hansel B, et al. Defective antioxidative activity of small

dense HDL3 particles in type 2 diabetes: relationship to elevated oxidative stress and

hyperglycaemia. Diabetologia. 2005;48(3):529-538.

21. Dungan KM, Guster T, DeWalt DA, Buse JB. A comparison of lipid and lipoprotein

measurements in the fasting and nonfasting states in patients with type 2 diabetes.

Curr Med Res Opin. 2007;23(11):2689-2695.

22. El Harchaoui K, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein

particle number and size as predictors of coronary artery disease in apparently

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First Lady Laura Bush sits with Lois Ingland, ...

First Lady Laura Bush sits with Lois Ingland, a heart disease survivor, during an event at the Carolinas Medical Center Wednesday, Feb. 15, 2006, in Charlotte, NC. Despite having none of the risk factors of heart disease, Lois, a mother of four, suffered a heart attack when she was 36 years old. (Photo credit: Wikipedia)

If you are hoping to lower your risk of a heart attack simply by raising your levels of “good” cholesterol—high-density lipoproteins (HDLs)—you may be disappointed. Although epidemiological studies point to HDLs as protective against heart disease, a new genetic analysis presented at the meeting shows that while high HDL might correlate with a healthier heart, it’s not itself responsible for lowering heart attack risks.

Source

Reported by: Dr. V.S.Karra, Ph.D

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