Voices from the Cleveland Clinic On Circulating apoA1: A Biomarker for a Proatherogenic Process in the Artery Wall
Curator: Aviva Lev-Ari, PhD, RN
UPDATED on 3/4/2019
People with Diabetes May Be Missing Out on HDL Cardiovascular Protections
Glycation lowers ApoA1 stability, destroys HDL in T2DM
A Cleveland Clinic study for the first time revealed a mechanism that rapidly destroys high-density lipoprotein (HDL) in people with Type 2 diabetes, negating cardiovascular protections of the so-called good cholesterol.
Sangeeta Kashyap, MD, in Cleveland Clinic’s Endocrinology & Metabolism Institute, and co-author Jonathan D. Smith, PhD, the Geoffrey Gund Endowed Chair for Cardiovascular Research in the Department of Cellular & Molecular Medicine in the Lerner Research Institute, and senior author Takhar Kasumov, PhD, adjunct in Gastroenterology and Hepatology at Cleveland Clinic and fulltime faculty at NEOMED, published a clinical research article in The Journal of Clinical Endocrinology & Metabolism.
The study, “Glycation Reduces the Stability of APOAI and Increases HDL Dysfunction in Diet-Controlled Type 2 Diabetes,” looks at the role of hyperglycemia-induced glycation on ApoA1 kinetics and stability in patients with diet-controlled type 2 diabetes mellitus (T2DM).
Derailing ApoA1
The study found that in people with diabetes, glycation of the ApoA1 molecule causes it to degrade three times faster than in a person without diabetes.
“When ApoA1 is destroyed faster, it is not able to perform its main function for reverse cholesterol uptake, which means taking the bad cholesterol and disposing of it,” says study co-author Sangeeta Kashyap, MD. “The bottom line is that it does not just matter how much good cholesterol you have, but how the cholesterol works to protect you. In people with diabetes, good cholesterol does not work normally to protect them from atherosclerotic heart disease.”
From a clinical perspective, Dr. Kashyap says, the data highlights that normal, or even elevated, HDL levels in T2DM does not equate to adequate functionality. Glycation of ApoA1, she says, is a marker for hyperglycemia-induced HDL dysfunction that blunts the anti-atherogenic and anti-oxidant functions of HDL.
These findings were reached using 2H20-metabolic labeling – a novel heavy water-based non-radioactive technique that looks at the kinetics of HDL by measuring the production and destruction of ApoA1. They study also found ApoA1 instability is related to early glycation of lysine on ApoA1 and associated with glycated hemoglobin (HbA1c) levels – a measure of long-term hyperglycemia.
When Good Cholesterol Goes Bad
“The important clinical piece for practitioners is that even if you see normal or high HDL levels, don’t think it’s working in their favor,” Dr. Kashyap says. “If they have high blood sugar, that’s a marker that HDL is not working to protect them from the atherogenic process.
Dr. Kashyap says lowering glucose levels could be a way to restore HDL functionality in people with diabetes. While previous articles theorized that high triglycerides were related to good cholesterol, this study found that HDL functionality is related to ambient glucose levels.
Reversing the Damage
Next steps involve looking at various glucose lowering interventions, including the effects of the diabetic drug Metformin and insulin, to lower glucose levels.
“We’re interested in looking at specific interventions to lower glucose levels to see if these defects are reversible. We believe they are,” Dr. Kashyap says. “This is an early glycation process. If we are able to lower blood sugar levels, we can reverse levels of lysine glycation of ApoAI and restore functionality of HDL.”
SOURCE
NATURE MEDICINE | ARTICLE
An abundant dysfunctional apolipoprotein A1 in human atheroma
Huang Y, DiDonato JA, Levison BS, et al. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med2014; published online December 26, 2014. DOI:10.1038/nm.3459. Abstract
- Ying Huang,
- Joseph A DiDonato,
- Bruce S Levison,
- Dave Schmitt,
- Lin Li,
- Yuping Wu,
- Jennifer Buffa,
- Timothy Kim,
- Gary S Gerstenecker,
- Xiaodong Gu,
- Chandra S Kadiyala,
- Zeneng Wang,
- Miranda K Culley,
- Jennie E Hazen,
- Anthony J DiDonato,
- Xiaoming Fu,
- Stela Z Berisha,
- Daoquan Peng,
- Truc T Nguyen,
- Shaohong Liang,
- Chia-Chi Chuang,
- Leslie Cho,
- Edward F Plow,
- Paul L Fox,
- Valentin Gogonea
- et al.
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
- Ying Huang,
- Joseph A DiDonato,
- Bruce S Levison,
- Dave Schmitt,
- Lin Li,
- Jennifer Buffa,
- Timothy Kim,
- Gary S Gerstenecker,
- Xiaodong Gu,
- Chandra S Kadiyala,
- Zeneng Wang,
- Miranda K Culley,
- Jennie E Hazen,
- Anthony J DiDonato,
- Xiaoming Fu,
- Stela Z Berisha,
- Daoquan Peng,
- Truc T Nguyen,
- Leslie Cho,
- Paul L Fox,
- Valentin Gogonea,
- W H Wilson Tang,
- Jonathan D Smith &
- Stanley L Hazen
-
Department of Mathematics, Cleveland State University, Cleveland, Ohio, USA.
- Yuping Wu
-
Department of Chemistry, Cleveland State University, Cleveland, Ohio, USA.
- Gary S Gerstenecker &
- Valentin Gogonea
-
Cleveland Heart Lab, Cleveland, Ohio, USA.
- Shaohong Liang
-
Department of Pathology, Section on Lipid Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- Chia-Chi Chuang &
- John S Parks
-
Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
- Leslie Cho,
- Edward F Plow,
- W H Wilson Tang,
- Jonathan D Smith &
- Stanley L Hazen
-
Department of Molecular Cardiology, Cleveland Clinic, Cleveland, Ohio, USA.
- Edward F Plow
-
Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- John S Parks
-
Department of Cardiovascular Medicine, New York University School of Medicine, New York, New York, USA.
- Edward A Fisher
Contributions
Y.H. participated in all laboratory, animal and human studies, assisted in statistical analyses, helped design the experiments and drafted the manuscript. B.S.L., G.S.G., V.G., C.S.K., Z.W. and X.F. assisted with various laboratory and mass spectrometry studies. D.S., J.B., M.K.C., S.Z.B. and C.-C.C. helped perform various animal experiments. J.A.D., D.S., T.K., X.G., M.K.C., J.E.H., A.J.D. and D.P. helped make various bacterial expression clones and produce and purify recombinant proteins used. J.A.D. and S.L. helped with mAb generation and screening. T.K. and T.T.N. helped with ELISA assays. L.L. and Y.W. provided statistical analyses of clinical data. J.A.D., L.C., E.F.P., P.L.F., V.G., W.H.W.T., J.S.P., E.A.F., J.D.S. and S.L.H. provided experimental analysis and expertise. All authors took part in critical review of the manuscript. The project was scientifically conceived and directed by S.L.H.
- Published online 26 January 2014
Recent studies have indicated that high-density lipoproteins (HDLs) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma are dysfunctional and are extensively oxidized by myeloperoxidase (MPO). In vitro oxidation of either apoA1 or HDL particles by MPO impairs their cholesterol acceptor function. Here, using phage display affinity maturation, we developed a high-affinity monoclonal antibody that specifically recognizes both apoA1 and HDL that have been modified by the MPO-H2O2-Cl− system. An oxindolyl alanine (2-OH-Trp) moiety at Trp72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirmed a critical role for apoA1 Trp72 in MPO-mediated inhibition of the ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation but accounts for 20% of the apoA1 in atherosclerosis-laden arteries. OxTrp72-apoA1 recovered from human atheroma or plasma is lipid poor, virtually devoid of cholesterol acceptor activity and demonstrated both a potent proinflammatory activity on endothelial cells and an impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n = 627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a proatherogenic process in the artery wall.
SOURCE
http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.3459.html
Interpretation of Results Findings in Heartwire
Oxidized, Dysfunctional HDL Evident in Atheroma
January 27, 2014
DRUG & REFERENCE INFORMATION
An assay for oxidized Trp72-apoA1 is expected to be available from Cleveland Heart Lab by the end of the year. What’s exciting about this assay, said Hazen, is that it detects not just a marker, but also a molecule involved in the disease process. If oxidized apoA1 can be measured and ultimately lowered, there is hope that doing so might reduce the risk of cardiovascular disease.The cardiovascular focus on raising HDL-cholesterol levels to prevent clinical events has been hit with disappointments in recent years, with numerous high-profile studies showing that while it’s possible to raise HDL-cholesterol levels with various agents, doing so does not translate into clinical benefit. One of the hypotheses behind such failures, including
- extended-release niacin in AIM-HIGH and HPS-2/THRIVE and
- two cholesterol ester transfer protein (CETP) inhibitors, dalcetrapib and torcetrapib,
has been that despite raising HDL-cholesterol levels, the HDL particle is dysfunctional.
Hazen, along with three coauthors, reports being a coinventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics or therapeutics. He is a paid consultant to AstraZeneca, Cleveland Heart Lab, Esperion, Lilly, Liposcience, Merck, Pfizer, Procter & Gamble, and Takeda. He reports research funding from the Cleveland Heart Lab, Liposcience, Procter & Gamble, and Takeda. Finally, Hazen reports the right to receive royalty payments for inventions/discoveries related to cardiovascular diagnostics or therapeutics from the Cleveland Heart Lab, Esperion, Frantz Biomarkers, and Liposcience . Other disclosures for the coauthors are listed in the online version of the paper.
- Barter, P.J. et al. Antiinflammatory properties of HDL. Circ. Res. 95, 764–772 (2004).
- Duffy, D. & Rader, D.J. Update on strategies to increase HDL quantity and function. Nat. Rev. Cardiol. 6, 455–463 (2009).
- Navab, M., Reddy, S.T., Van Lenten, B.J. & Fogelman, A.M. HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat. Rev. Cardiol. 8, 222–232(2011).
- Khera, A.V. et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 364, 127–135 (2011).
- Vickers, K.C., Palmisano, B.T., Shoucri, B.M., Shamburek, R.D. & Remaley, A.T. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol. 13, 423–433 (2011).
- Fisher, E.A., Feig, J.E., Hewing, B., Hazen, S.L. & Smith, J.D. High-density lipoprotein function, dysfunction, and reverse cholesterol transport. Arterioscler. Thromb. Vasc. Biol. 32,2813–2820 (2012).
- Gordon, T., Castelli, W.P., Hjortland, M.C., Kannel, W.B. & Dawber, T.R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study.Am. J. Med. 62, 707–714 (1977).
- Badimon, J.J., Badimon, L., Galvez, A., Dische, R. & Fuster, V. High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits. Lab. Invest. 60,455–461 (1989).
- Badimon, J.J., Badimon, L. & Fuster, V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J. Clin. Invest. 85, 1234–1241(1990).
- Rubin, E.M., Krauss, R.M., Spangler, E.A., Verstuyft, J.G. & Clift, S.M. Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature 353, 265–267 (1991).
- Plump, A.S., Scott, C.J. & Breslow, J.L. Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E–deficient mouse. Proc. Natl. Acad. Sci. USA 91, 9607–9611 (1994).
- Hughes, S.D., Verstuyft, J. & Rubin, E.M. HDL deficiency in genetically engineered mice requires elevated LDL to accelerate atherogenesis. Arterioscler. Thromb. Vasc. Biol. 17,1725–1729 (1997).
- Nissen, S.E. et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. J. Am. Med. Assoc.290, 2292–2300 (2003).
- Sacks, F.M. et al. Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo. J. Lipid Res. 50, 894–907 (2009).
- Tardif, J.C. et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. J. Am. Med. Assoc. 297, 1675–1682 (2007).
- Barter, P.J. et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2122 (2007).
- Nissen, S.E. et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N. Engl. J. Med. 356, 1304–1316 (2007).
- Boden, W.E. et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365, 2255–2267 (2011).
- Voight, B.F. et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 380, 572–580 (2012).
- Bhattacharyya, T. et al. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. J. Am. Med. Assoc.299, 1265–1276 (2008).
- Besler, C. et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J. Clin. Invest. 121, 2693–2708 (2011).
- Sorci-Thomas, M.G. & Thomas, M.J. High density lipoprotein biogenesis, cholesterol efflux, and immune cell function. Arterioscler. Thromb. Vasc. Biol. 32, 2561–2565 (2012).
- Shih, D.M. et al. Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis. J. Biol. Chem. 275, 17527–17535(2000).
- Tang, W.H. et al. Clinical and genetic association of serum paraoxonase and arylesterase activities with cardiovascular risk. Arterioscler. Thromb. Vasc. Biol. 32, 2803–2812 (2012).
- DiDonato, J.A. et al. Function and distribution of apolipoprotein A1 in the artery wall are markedly distinct from those in plasma. Circulation 128, 1644–1655 (2013).
- Zheng, L. et al. Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J. Clin. Invest.114, 529–541 (2004).
- Wu, Z. et al. The refined structure of nascent HDL reveals a key functional domain for particle maturation and dysfunction. Nat. Struct. Mol. Biol. 14, 861–868 (2007).
- Peng, D.Q. et al. Apolipoprotein A-I tryptophan substitution leads to resistance to myeloperoxidase-mediated loss of function. Arterioscler. Thromb. Vasc. Biol. 28, 2063–2070(2008).
- Undurti, A. et al. Modification of high density lipoprotein by myeloperoxidase generates a pro-inflammatory particle. J. Biol. Chem. 284, 30825–30835 (2009).
- Hadfield, K.A. et al. Myeloperoxidase-derived oxidants modify apolipoprotein A-I and generate dysfunctional high-density lipoproteins: comparison of hypothiocyanous acid (HOSCN) with hypochlorous acid (HOCl). Biochem. J. 449, 531–542 (2013).
- Van Lenten, B.J. et al. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. Loss of protective effect of HDL against LDL oxidation in aortic wall cell cocultures. J. Clin. Invest. 96, 2758–2767 (1995).
- Ansell, B.J. et al. Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment. Circulation 108, 2751–2756(2003).
- Charles-Schoeman, C. et al. Effects of high-dose atorvastatin on antiinflammatory properties of high density lipoprotein in patients with rheumatoid arthritis: a pilot study. J. Rheumatol.34, 1459–1464 (2007).
- Shao, B., Pennathur, S. & Heinecke, J.W. Myeloperoxidase targets apolipoprotein A-I, the major high density lipoprotein protein, for site-specific oxidation in human atherosclerotic lesions. J. Biol. Chem. 287, 6375–6386 (2012).
- Brennan, M.L. et al. A tale of two controversies: defining both the role of peroxidases in nitrotyrosine formation in vivo using eosinophil peroxidase and myeloperoxidase-deficient mice, and the nature of peroxidase-generated reactive nitrogen species. J. Biol. Chem. 277,17415–17427 (2002).
- Timmins, J.M. et al. Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I. J. Clin. Invest. 115,1333–1342 (2005).
- Barter, P.J. & Kastelein, J.J. Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease. J. Am. Coll. Cardiol. 47, 492–499 (2006).
- Bergt, C. et al. The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport. Proc. Natl. Acad. Sci. USA101, 13032–13037 (2004).
- Shao, B. et al. Tyrosine 192 in apolipoprotein A-I is the major site of nitration and chlorination by myeloperoxidase, but only chlorination markedly impairs ABCA1-dependent cholesterol transport. J. Biol. Chem. 280, 5983–5993 (2005).
- Cybulsky, M.I. et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J. Clin. Invest. 107, 1255–1262 (2001).
- Segrest, J.P. et al. A detailed molecular belt model for apolipoprotein A-I in discoidal high density lipoprotein. J. Biol. Chem. 274, 31755–31758 (1999).
- Wu, Z. et al. Double superhelix model of high density lipoprotein. J. Biol. Chem. 284,36605–36619 (2009).
- Gogonea, V. et al. Congruency between biophysical data from multiple platforms and molecular dynamics simulation of the double-super helix model of nascent high-density lipoprotein. Biochemistry 49, 7323–7343 (2010).
- Wu, Z. et al. The low resolution structure of ApoA1 in spherical high density lipoprotein revealed by small angle neutron scattering. J. Biol. Chem. 286, 12495–12508 (2011).
- Gogonea, V. et al. The low-resolution structure of nHDL reconstituted with DMPC with and without cholesterol reveals a mechanism for particle expansion. J. Lipid Res. 54, 966–983(2013).
- Pattison, D.I. & Davies, M.J. Absolute rate constants for the reaction of hypochlorous acid with protein side chains and peptide bonds. Chem. Res. Toxicol. 14, 1453–1464 (2001).
- Baldus, S. et al. Endothelial transcytosis of myeloperoxidase confers specificity to vascular ECM proteins as targets of tyrosine nitration. J. Clin. Invest. 108, 1759–1770 (2001).
- Abu-Soud, H.M. & Hazen, S.L. Nitric oxide is a physiological substrate for mammalian peroxidases. J. Biol. Chem. 275, 37524–37532 (2000).
- Eiserich, J.P. et al. Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science 296,2391–2394 (2002).
- Wang, Y. et al. Myeloperoxidase inactivates TIMP-1 by oxidizing its N-terminal cysteine residue: an oxidative mechanism for regulating proteolysis during inflammation. J. Biol. Chem. 282, 31826–31834 (2007).
- Sugiyama, S. et al. Hypochlorous acid, a macrophage product, induces endothelial apoptosis and tissue factor expression: involvement of myeloperoxidase-mediated oxidant in plaque erosion and thrombogenesis. Arterioscler. Thromb. Vasc. Biol. 24, 1309–1314 (2004).
- Nahrendorf, M. et al. Activatable magnetic resonance imaging agent reports myeloperoxidase activity in healing infarcts and noninvasively detects the antiinflammatory effects of atorvastatin on ischemia-reperfusion injury. Circulation 117, 1153–1160 (2008).
- Ronald, J.A. et al. Enzyme-sensitive magnetic resonance imaging targeting myeloperoxidase identifies active inflammation in experimental rabbit atherosclerotic plaques. Circulation 120,592–599 (2009).
- Hazen, S.L. & Heinecke, J.W. 3-chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima. J. Clin. Invest. 99, 2075–2081 (1997).
- Zamanian-Daryoush, M. et al. The cardioprotective protein apolipoprotein A1 promotes potent anti-tumorigenic effects. J. Biol. Chem. 288, 21237–21252 (2013).
- Markwell, M.A., Haas, S.M., Bieber, L.L. & Tolbert, N.E. A modification of the Lowry procedure to simplify protein determination in membrane and lipoprotein samples. Anal. Biochem. 87, 206–210 (1978).
- Ryan, R.O., Forte, T.M. & Oda, M.N. Optimized bacterial expression of human apolipoprotein A-I. Protein Expr. Purif. 27, 98–103 (2003).
- Matz, C.E. & Jonas, A. Micellar complexes of human apolipoprotein A-I with phosphatidylcholines and cholesterol prepared from cholate-lipid dispersions. J. Biol. Chem.257, 4535–4540 (1982).
- Köhler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).
- Todorovski, T., Fedorova, M., Hennig, L. & Hoffmann, R. Synthesis of peptides containing 5-hydroxytryptophan, oxindolylalanine, N-formylkynurenine and kynurenine. J. Pept. Sci. 17,256–262 (2011).
- Ståhlman, M. et al. Proteomics and lipids of lipoproteins isolated at low salt concentrations in D2O/sucrose or in KBr. J. Lipid Res. 49, 481–490 (2008).
- Robinet, P., Wang, Z., Hazen, S.L. & Smith, J.D. A simple and sensitive enzymatic method for cholesterol quantification in macrophages and foam cells. J. Lipid Res. 51, 3364–3369(2010).
- Barbas, C.F. III, Burton, D.R., Scott, J.K. & Silverman, G.J. Phage Display: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2001).
- Marks, J.D. et al. By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J. Mol. Biol. 222, 581–597 (1991).
- Chung, S. et al. Targeted deletion of hepatocyte ABCA1 leads to very low density lipoprotein triglyceride overproduction and low density lipoprotein hypercatabolism. J. Biol. Chem. 285,12197–12209 (2010).
Other articles on Apo1 and HDL published on this Open Access Online Scientific Journal include the following:
LDL, HDL, TG, ApoA1 and ApoB: Genetic Loci Associated With Plasma Concentration of these Biomarkers – A Genome-Wide Analysis With Replication
Aviva Lev-Ari, PhD, RN
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
Voice from the Cleveland Clinic: On the New Lipid Guidelines and On the ACC/AHA Risk Calculator
Aviva Lev-Ari, PhD, RN
Endothelial Dysfunction (release into the circulation of damaged endothelial cells) as A Risk Marker for Ischemia and MI
Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2014/01/12/endothelial-dysfunction-as-risk-marker/
Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles
Aviva Lev-Ari, PhD, RN
Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore
Aviva Lev-Ari, PhD, RN
Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD
Aviva Lev-Ari, PhD, RN
Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients
Aviva Lev-Ari, PhD, RN
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
Lp(a) Gene Variant Association
Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2013/03/06/10447/
Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging
Aviva Lev-Ari, PhD, RN
Assessing Cardiovascular Disease with Biomarkers
Larry H Bernstein, MD, FCAP
http://pharmaceuticalintelligence.com/2012/12/25/assessing-cardiovascular-disease-with-biomarkers/
Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment
Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
What is the role of plasma viscosity in hemostasis and vascular disease risk?
Larry H Bernstein, MD and Aviva Lev-Ari, PhD, RN
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