Life Extension Magazine®

Issue: Jun 2015

The Value of Testing Beyond Cholesterol and LDL For The Prevention of Heart Disease

Standard cholesterol blood tests do not measure levels of oxidized LDL, which carries significant vascular risk. Blood tests for oxidized LDL were previously available only at specialized research labs. Now, Life Extension® members can access this lifesaving test that helps measure heart attack risk at an affordable cost.

By Scott Fogle, ND

Preamble By William Faloon

This article describes newly available blood tests that will likely save the lives of millions of humans if they are incorporated into widespread screenings of the general population.

Standard blood tests measure the amount of LDL in one’s blood. They do not, however, reveal the degree to which the LDL is oxidized or other factors that increase LDL’s vascular risk profile.

New tests are available to measure these atherogenic variables. These tests are suited for people with existing vascular disease, those with family histories of heart disease or other risks of heart problems, and for individuals who can afford the additional cost.

At this time, we don’t know if all Life Extension® members need these new tests that measure oxidized LDL (and its byproducts). That’s because the nutrients members already take may be sufficiently neutralizing these forms of atherogenic risk.

Once Life Extension®’s medical experts review members’ results, we’ll be able to determine which individuals may be at higher risk for having oxidized LDL and the steps needed to reverse this common cause of arterial occlusion.

Doctor’s today routinely measure cholesterol levels with a standard lipid profile blood test. But this test omits some diagnostic information that could leave you at significant cardiovascular risk.1,2

A much better approach is to directly measure the oxidized fats and their immediate consequences within arteries.3,4 New studies are revealing the dangerous association between three fundamental measures of lipid oxidation and increased heart disease risk.

These three new tests measure:3-5

  1. Oxidized LDL
  2. Myeloperoxidase
  3. F2-isoprostanes

These three tests assess vascular damage as well as markers of oxidized fat in the blood, which provides predictive value for cardiovascular disease that goes beyond standard lipid panel testing.3,4,6

For many years these cutting-edge tests were not available to the public. They were used primarily at universities for research and were far too expensive for general use. However, Life Extension® has worked long and hard to bring these innovative tests to its members to help further diagnose and reduce potential risk factors for cardiovascular disease.

Testing For Oxidized LDL Cholesterol

Testing For Oxidized LDL Cholesterol  

We have long known that oxidized LDL (OxLDL) triggers dangerous inflammatory changes that lead to atherosclerosis.7,8 But most physicians were unable to test for this cardiac risk factor as the test was expensive and restricted to research labs and universities. OxLDL is now proving to be a risk predictor for metabolic syndrome, cardiovascular disease in general,9-11 and acute myocardial infarction (heart attack) in particular.12

Oxidized cholesterol (OxLDL) levels show a strong correlation with having acute coronary syndromes (angina, or chest pain, ischemia, or evidence of low blood flow on ECG) and the risk of heart attacks.8 In fact, the higher the OxLDL level, the more severe the signs and symptoms of heart disease. People with more advanced ischemic heart disease show significantly more OxLDL in the macrophages.8 And the higher the OxLDL level in blood13 and plaques, the greater the risk of plaque rupture, with devastating consequence.14,15 Higher OxLDL levels should raise concern and prompt interventions to extinguish this vascular risk factor.

Measuring OxLDL is now possible with a simple blood test. Research shows that even apparently healthy men with elevated OxLDL levels have a more than 4-fold increased risk for a future coronary heart disease event compared with those with the lowest levels.16 What makes this test so important for avoiding heart disease is that plasma OxLDL is a stronger predictor of such events than a conventional cholesterol blood test.16 As OxLDL levels rise, so does the presence and extent of coronary artery disease; that risk is three times greater for those with the highest versus the lowest OxLDL levels, and nearly 17 times as great in those who also have high cholesterol.15

OxLDL levels also predict your risk of having metabolic syndrome, that combination of being overweight and hypertension with disturbed regulation of blood sugar and lipids that dramatically raises risk for heart disease, stroke, diabetes, and cancer.17-19 One study showed that those with the highest levels were at nearly four times the risk for metabolic syndrome than were those with the lowest.20

What You Need To Know
Testing Beyond Cholesterol and LDL

Testing Beyond Cholesterol and LDL

  • Knowing your lipid profile numbers is an important way to identify your risk for cardiovascular disease.
  • But a standard lipid profile can only provide general information, based on population-level statistics.
  • More personalized and individual assessment of your cardiovascular risk provides unique insights.
  • Newly available advanced risk factor testing can now evaluate oxidized LDL and myeloperoxidase, and/or urinary F2-isoprostanes.
  • These tests can more accurately detect hidden risks for cardiovascular disease, even in people with normal traditional lipid profiles.
  • You can take steps through diet, exercise, and supplementation to lower your risk levels based on these tests.

Myeloperoxidase: A Direct Measure Of Arterial Damage

Myeloperoxidase (MPO) is an enzyme produced by inflammation-generating white blood cells in your body.21 The enzyme demonstrates a wide range of atherosclerosis-promoting effects, including production of OxLDL and oxidized HDL cholesterol and increased fragility of plaque lesions.1,2,22,23 MPO also reduces the availability of nitric oxide,24 a signaling molecule that tells blood vessels to relax and lower blood pressure.25,26

When arterial walls are damaged by elevated pressure,27 plaque, or even inflammation28 alone, white blood cells invade to repair the damage, releasing MPO.29 MPO is a direct measure of plaque-promoting blood vessel inflammation; it also activates enzymes that degrade the protein-rich “cap” on arterial plaques,30 making them increasingly vulnerable to catastrophic rupture.31,32

MPO levels are significantly higher in apparently healthy adults who go on to develop coronary artery disease. Those with the highest MPO levels have a nearly 50% increase in risk versus those with the lowest.2,6 Of extreme importance, the increased risk associated with elevated MPO levels was seen even in people with normal LDL, HDL, and CRP measurements.2

Similarly, in people with chest pain or ECG abnormalities, a raised MPO level predicted the risk of a heart attack even when they had normal levels of troponin T, a marker of heart muscle injury frequently used in emergency rooms to detect an early heart attack.22,33,34 In other words, MPO elevations revealed hidden risk in people who otherwise would have thought their arteries were in good shape. Such early detection can help people make important changes to reduce their risk.

People with acute coronary syndrome (chest pain and/or ECG changes, even without a heart attack) are at vastly increased risk for developing a heart attack in the near future.35,36 With that said, there is always a need to identify new and accurate independent biomarkers that predict heart attack risk.37

Measuring MPO can reveal a person’s risk more accurately. By way of example, people with acute coronary syndrome with MPO levels below about 20 ng/mL have an 88% chance of evading a heart attack over the next 24 months, compared with a 74% chance of such survival in those with elevated MPO levels.37 Those with the highest MPO levels have a 2.4-fold increase in their risk for dying of cardiovascular disease over 13 years versus those with the lowest levels.4

Combining MPO, which provides direct evidence of arterial damage, with C-reactive protein (CRP), a more general measure of inflammation, can further refine an individual’s risk prediction for cardiovascular disease: Having both MPO and CRP elevated puts you at more than four times the risk of dying from heart disease.4

Taken together, these figures suggest that MPO can be used to give you a lifesaving early warning to turn your cardiovascular health around while there’s still time.

Interpreting Your Test Results
Interpreting Your Test Results

Here are some numbers to help you interpret the results of your advanced testing for cardiovascular disease.

Oxidized LDL (OxLDL): If your level is less than 60 U/L, your risk is considered low; from 60 to 69 defines moderate risk, and levels of 70 or higher put you at high risk.68

Myeloperoxidase (MPO): A level below 480 pmol/L indicates normal risk, while 480 or higher suggests increased cardiovascular risk.69

F2-isoprostanes: Your risk is low when your level is less than 0.86 ng/mg; at or above that level places you at high risk.70

F2-isoprostanes: Detecting A Culprit In Vascular Inflammation

Your body uses signaling molecules to announce the presence of damaged tissue and to trigger the healthy inflammatory response.38,39 Cytokines,40 leukotrienes,41 and prostaglandins42 are all families of such pro-inflammatory signals. Under normal circumstances, these molecules are degraded and disappear, ending the inflammatory stimulus. But if inflammation-promoting molecules continue to be manufactured, the inflammation will persist, leading to long-term damage.

One of the major sources of inflammatory prostaglandins is arachidonic acid, a major component of cell membranes.43

In the presence of oxidizing free radicals, prostaglandin-like molecules called F2-isoprostanes can be produced from arachidonic acid resulting in unregulated outpourings of this pro-inflammatory signal.44-46

The damage done by F2-isoprostanes is not restricted to blood vessel inflammation. Like their normal prostaglandin counterparts, F2-isoprostanes promote the clumping of platelets, the tiny cell fragments in blood that participate in the clotting mechanism. Under the stimulus of F2-isoprostanes, platelets clump more aggressively, contributing to increased risk of arterial blockage, particularly at the site of an existing plaque.45,47,48 Note that, because formation of F2-isoprostanes does not require the COX enzyme, the use of COX-inhibiting medications like aspirin will not counteract the platelet effects, rendering useless an important form of prevention in cardiovascular disease.47

F2-isoprostanes are easily measured in a urine specimen, making them especially attractive as a means for long-term monitoring of cardiovascular risk. People with elevated urinary F2-isoprostanes are at a more than 30-fold risk for developing coronary heart disease compared with those with normally low levels.3

People who smoke49 and those who eat red meat,50 both known cardiovascular risk factors, have been shown to have significantly higher plasma or urinary F2-isoprostanes than do people with healthier lifestyle habits, while those who regularly exercise have lower levels.46,51,52 Intriguingly, it is becoming evident that high urinary F2-isoprostanes also signal an increased risk of certain cancers, further attestation to the powerful interactions of oxidative damage and inflammation in the body.53,54

Why Oxidized Cholesterol Is Dangerous

If you have ever smelled rancid butter, cooking oil, or grease, you have experienced first-hand the impact of oxidation on fats. Fat molecules are especially vulnerable to oxygen,71 which is found in abundance in arterial blood. When the fat and oxidation come together, the resulting chemical reactions change the shape and the function of fat molecules.72 Your body tries to handle oxidized fat molecules with antioxidants, but if the antioxidants become overwhelmed, then the cholesterol molecules including LDL and HDL become oxidized. This oxidized LDL will damage the walls of the artery. Once there, specialized cells called macrophages identify oxidized fats as “foreign” materials, and engulf them to take them out of circulation.73,74 But these oxidized LDL laden macrophages can accumulate in the arterial wall, beneath the delicate endothelial layer, where they reside as so-called foam cells.75,76 And foam cells, in turn, trigger inflammatory changes in the arterial wall, which eventually lead to the formation of an inflammatory plaque.16, 77-79 Since oxidized LDL is a powerful initiator of this devastating process, it is important to keep oxidized LDL levels at a minimum.

Inflammatory plaque contains white blood cells and cellular debris, along with inflammatory signaling molecules.80-82 Drawn by oxidized fats, macrophages from the immune system swarm into the inflamed plaque area, consume the oxidized LDL, release toxic chemicals that cause swelling and inflammation and form foam cells.14 These foam cells then die creating debris that fill the inflamed tissue and perpetuate even more inflammation.81,83 Levels of oxidized LDL cholesterol within plaques are nearly 70 times greater than in circulating blood.14

An inflammatory plaque bulging into an artery can significantly reduce blood flow through that artery.84,85 Worse, if the plaque ruptures, it sends a shower of debris, including oxidized fats, cell fragments, and clumped platelets, downstream to where it can become trapped in the narrowing vessel. When that happens, blood flow suddenly becomes reduced or blocked and the victim experiences a heart attack (myocardial infarction) or an ischemic stroke.86-88 The recent onset of inflammation affecting atherosclerotic plaques is known to be related to acute coronary syndromes (including chest pain, characteristic ECG changes, and eventually heart attack).8

Currently, doctors measure levels of inflammation in order to try to understand a person’s cardiovascular risk in the face of apparently normal lipid levels.89,90 Such measurements reinforce the connections between oxidation, inflammation, and cardiovascular disease. For example, among apparently healthy men, those with the highest baseline levels of inflammation, as measured by C-reactive protein (CRP), were at a nearly 3-fold risk of heart attack and almost double the risk of ischemic stroke, compared with those at the lowest levels of inflammation.91 Similar risk elevations of 2- to 3-fold have been shown in other studies measuring inflammatory changes in addition to standard lipid levels.89, 90,92 Mainstream medicine has finally begun to target inflammation as a drug-treatable risk factor for atherosclerosis.93

What To Do If Oxidation-Inflammation Levels Are Elevated

Testing for blood levels of oxidized LDL (OxLDL), myeloperoxidase (MPO), and urinary F2-isoprostanes provides tremendous insight into what is going on at the molecular level in one’s body.

If your levels are elevated, you’ll find precious little help from mainstream medicine, despite its enormous stock of chemical drugs.

A better approach is to choose from among the growing list of supplements that are proven to reduce these markers (and mediators) of cardiovascular disease. Here is a partial listing of supplements that can reduce markers of lipid oxidation:

  • Omega-3 fatty acids from fish oil55
  • Vitamin E56
  • Gamma tocopherol combined with sesame lignans57
  • L-carnitine58
  • Zinc59
  • Grape seed extracts and/or resveratrol60,61
  • Pomegranate62
  • Superoxide dismutase (SOD)63
  • CoQ1064
  • Whole grape extracts65
  • Indian gooseberry66

Summary

Measurement of blood cholesterol, LDL, HDL, and triglycerides (lipid profile) as a means of identifying people at high risk for cardiovascular disease is more than four decades old.67 There is no doubt that early detection and intervention has saved lives. But in today’s world, simply knowing your cholesterol levels provides only partial protection.

Low cholesterol and LDL levels may not indicate safety, while elevated levels may not paint an accurate picture of the true risk situation. More precise markers of cardiovascular risk are now available at relatively affordable prices.

  • Measurements of oxidized LDL (OxLDL) offer insights into how much damage is being done to the lipids in your bloodstream.
  • Measurement of myeloperoxidase (MPO) can indicate the impact of inflammatory changes on your blood vessels.
  • Measurements of F2-isoprostanes in a urine specimen can tell you to what extent your body’s own fat molecules are participating in inflammatory changes that can dramatically affect your health.

You now have the following options that can be added to the recommended Male or Female Panels:

Oxidized LDL
Item #LC817472
Retail Price: $100.00
Member Price $75.00
Super Sale Price: $56.25
(valid when ordered by June 1, 2015)

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Oxidized LDL Panel
(Myeloperoxidase)

Item #LC100034
Retail Price: $233.33
Member Price: $175.00
Super Sale Price: $131.25
(valid when ordered by June 1, 2015)

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Advanced Oxidized
LDL Panel
(F2-isoprostanes, Oxidized LDL
And Myeloperoxidase Panel)

Item #LC100035
Retail Price: $380.00
Member Price: $285.00
Super Sale Price: $213.75
(valid when ordered by June 1, 2015)

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If any result comes back elevated, you are in a position to initiate a sensible program of dietary changes, regular exercise, and appropriate nutritional supplements.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

Dr. Scott Fogle is the Director of Clinical Information and Laboratory Services at Life Extension®, where he oversees scientific and medical information as well as its laboratory division.

References

  1. Zheng L, Nukuna B, Brennan ML, et al. Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J Clin Invest. 2004 Aug;114(4):529-41.
  2. Meuwese MC, Stroes ES, Hazen SL, et al. Serum myeloperoxidase levels are associated with the future risk of coronary artery disease in apparently healthy individuals: the EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol. 2007 Jul 10;50(2):159-65.
  3. Schwedhelm E, Bartling A, Lenzen H, et al. Urinary 8-iso-prostaglandin F2alpha as a risk marker in patients with coronary heart disease: a matched case-control study. Circulation. 2004 Feb 24;109(7):843-8.
  4. Heslop CL, Frohlich JJ, Hill JS. Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography. J Am Coll Cardiol. 2010 Mar 16;55(11):1102-9.
  5. Davies SS, Roberts LJ 2nd. F2-isoprostanes as an indicator and risk factor for coronary heart disease. Free Radic Biol Med. 2011 Mar 1;50(5):559-66.
  6. Karakas M, Koenig W, Zierer A, et al. Myeloperoxidase is associated with incident coronary heart disease independently of traditional risk factors: results from the MONICA/KORA Augsburg study. J Intern Med. 2012 Jan;271(1):43-50.
  7. Kiyan Y, Tkachuk S, Hilfiker-Kleiner D, Haller H, Fuhrman B, Dumler I. oxLDL induces inflammatory responses in vascular smooth muscle cells via urokinase receptor association with CD36 and TLR4. J Mol Cell Cardiol. 2014 Jan;66:72-82.
  8. Ehara S, Ueda M, Naruko T, et al. Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes. Circulation. 2001 Apr 17;103(15):1955-60.
  9. Ueba T, Nomura S, Nishikawa T, Kajiwara M, Yamashita K. Circulating oxidized LDL, measured with FOH1a/DLH3 antibody, is associated with metabolic syndrome and the coronary heart disease risk score in healthy Japanese. Atherosclerosis. 2009 Mar;203(1):243-8.
  10. Holvoet P, Lee DH, Steffes M, Gross M, Jacobs DR Jr. Association between circulating oxidized low-density lipoprotein and incidence of the metabolic syndrome. JAMA. 2008 May 21;299(19):2287-93.
  11. Trpkovic A, Resanovic I, Stanimirovic J, et al. Oxidized low-density lipoprotein as a biomarker of cardiovascular diseases. Crit Rev Clin Lab Sci. 2014 Dec 24:1-16.
  12. Holvoet P, Kritchevsky SB, Tracy RP, et al. The metabolic syndrome, circulating oxidized LDL, and risk of myocardial infarction in well-functioning elderly people in the health, aging, and body composition cohort. Diabetes. 2004 Apr;53(4):1068-73.
  13. Tsimikas S, Bergmark C, Beyer RW, et al. Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes. J Am Coll Cardiol. 2003 Feb 5;41(3):360-70.
  14. Nishi K, Itabe H, Uno M, et al. Oxidized LDL in carotid plaques and plasma associates with plaque instability. Arterioscler Thromb Vasc Biol. 2002 Oct 1;22(10):1649-54.
  15. Tsimikas S, Brilakis ES, Miller ER, et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med. 2005 Jul 7;353(1):46-57.
  16. Meisinger C, Baumert J, Khuseyinova N, Loewel H, Koenig W. Plasma oxidized low-density lipoprotein, a strong predictor for acute coronary heart disease events in apparently healthy, middle-aged men from the general population. Circulation. 2005 Aug 2;112(5):651-7.
  17. Hofmann SM, Tschöp MH. Dietary sugars: a fat difference. J Clin Invest. 2009 May;119(5):1089-92.
  18. Esposito K, Chiodini P, Colao A, Lenzi A, Giugliano D. Metabolic syndrome and risk of cancer: a systematic review and meta analysis. Diabetes Care . 2012 Nov;35(11):2402-11.
  19. Air EL, Kissela BM. Diabetes, the metabolic syndrome, and ischemic stroke: epidemiology and possible mechanisms. Diabetes Care. 2007 Dec;30(12):3131-40. Epub 2007 Sep 11. Review.
  20. Holvoet P, Lee DH, Steffes M, Gross M, Jacobs DR, Jr. Association between circulating oxidized low-density lipoprotein and incidence of the metabolic syndrome. Jama. 2008 May 21;299(19):2287-93.
  21. Mayyas FA, Al-Jarrah MI, Ibrahim KS, Alzoubi KH. Level and significance of plasma myeloperoxidase and the neutrophil to lymphocyte ratio in patients with coronary artery disease. Exp Ther Med. 2014 Dec;8(6):1951-7.
  22. Baldus S, Heeschen C, Meinertz T, et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation. 2003 Sep 23;108(12):1440-5.
  23. Sugiyama S, Kugiyama K, Aikawa M, Nakamura S, Ogawa H, Libby P. 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. 2004 Jul;24(7):1309-14.
  24. Rudolph TK, Wipper S, Reiter B, et al. Myeloperoxidase deficiency preserves vasomotor function in humans. Eur Heart J. 2012 Jul;33(13):1625-34.
  25. Eiserich JP, Baldus S, Brennan ML, et al. Myeloperoxidase, a leukocyte-derived vascular NO oxidase. Science. 2002 Jun 28;296(5577):2391-4.
  26. Podrez EA, Schmitt D, Hoff HF, Hazen SL. Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro. J Clin Invest. 1999 Jun;103(11):1547-60.
  27. Shen K, Sung KL, Whittemore DE, DeLano FA, Zweifach BW, Schmid-Schönbein GW. Properties of circulating leukocytes in spontaneously hypertensive rats. Biochem Cell Biol. 1995 Jul-Aug;73(7-8):491-500.
  28. Lau D, Mollnau H, Eiserich JP, et al. Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins. Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):431-6.
  29. Tavora FR, Ripple M, Li L, Burke AP. Monocytes and neutrophils expressing myeloperoxidase occur in fibrous caps and thrombi in unstable coronary plaques. BMC Cardiovasc Disord. 2009;9:27.
  30. Heslop CL, Frohlich JJ, Hill JS. Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography. J Am Coll Cardiol. 2010 Mar 16;55(11):1102-9.
  31. Hazen SL, Heinecke JW. 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima. J Clin Invest. 1997 May 1;99(9):2075-81.
  32. Fu X, Kassim SY, Parks WC, Heinecke JW. Hypochlorous acid oxygenates the cysteine switch domain of pro-matrilysin (MMP-7). A mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by myeloperoxidase. J Biol Chem. 2001 Nov 2;276(44):41279-87.
  33. Brennan ML, Penn MS, Van Lente F, et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med. 2003 Oct 23;349(17):1595-604.
  34. Mair J, Dienstl F, Puschendorf B. Cardiac troponin T in the diagnosis of myocardial injury. Crit Rev Clin Lab Sci. 1992;29(1):31-57.
  35. Knudtson ML, Norris CM, Galbraith PD, Hubacek J, Ghali WA. Explicit risk in acute coronary syndrome management. Can J Cardiol. 2009 Jun;25 Suppl A:29A-36A.
  36. Edmondson D, Shaffer JA, Denton EG, Shimbo D, Clemow L. Posttraumatic stress and myocardial infarction risk perceptions in hospitalized acute coronary syndrome patients. Front Psychol. 2012 May 14;3:144.
  37. Cavusoglu E, Ruwende C, Eng C, et al. Usefulness of baseline plasma myeloperoxidase levels as an independent predictor of myocardial infarction at two years in patients presenting with acute coronary syndrome. Am J Cardiol. 2007 May 15;99(10):1364-8.
  38. Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. 2014 Mar 1;20(7):1126-67.
  39. Napoleão P, Santos MC, Selas M, Viegas-Crespo AM, Pinheiro T, Ferreira RC. Variations in inflammatory markers in acute myocardial infarction: a longitudinal study. Rev Port Cardiol. 2007 Dec;26(12):1357-63.
  40. Dinarello CA. Proinflammatory cytokines. Chest. 2000 Aug;118(2):503-8.
  41. Eun JC, Moore EE, Banerjee A, et al. Leukotriene b4 and its metabolites prime the neutrophil oxidase and induce proinflammatory activation of human pulmonary microvascular endothelial cells. Shock. 2011 Mar;35(3):240-4.
  42. Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. 2011 May;31(5):986-1000.
  43. Brash AR. Arachidonic acid as a bioactive molecule. J Clin Invest. 2001 Jun;107(11):1339-45.
  44. Morrow JD, Hill KE, Burk RF, Nammour TM, Badr KF, Roberts LJ, 2nd. A series of prostaglandin F2-like compounds are produced in vivo in humans by a non-cyclooxygenase, free radical-catalyzed mechanism. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9383-7.
  45. Minuz P, Andrioli G, Degan M, et al. The F2-isoprostane 8-epiprostaglandin F2alpha increases platelet adhesion and reduces the antiadhesive and antiaggregatory effects of NO. Arterioscler Thromb Vasc Biol. 1998 Aug;18(8):1248-56.
  46. Morrow JD, Frei B, Longmire AW, et al. Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage. N Engl J Med. 1995 May 4;332(18):1198-203.
  47. Morrow JD, Minton TA, Roberts LJ, 2nd. The F2-isoprostane, 8-epi-prostaglandin F2 alpha, a potent agonist of the vascular thromboxane/endoperoxide receptor, is a platelet thromboxane/endoperoxide receptor antagonist. Prostaglandins. 1992 Aug;44(2):155-63.
  48. Morrow JD, Awad JA, Boss HJ, Blair IA, Roberts LJ 2nd. Non-cyclooxygenase-derived prostanoids (F2-isoprostanes) are formed in situ on phospholipids. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10721-5.
  49. Taylor AW, Bruno RS, Traber MG. Women and smokers have elevated urinary F(2)-isoprostane metabolites: a novel extraction and LC-MS methodology. Lipids. 2008 Oct;43(10):925-36.
  50. Meyer KA, Sijtsma FP, Nettleton JA, Steffen LM, Van Horn L, Shikany JM, Gross MD, Mursu J, Traber MG, Jacobs DR Jr. Dietary patterns are associated with plasma F₂-isoprostanes in an observational cohort study of adults. Free Radic Biol Med. 2013 Apr;57:201-9.
  51. Tappel A. Heme of consumed red meat can act as a catalyst of oxidative damage and could initiate colon, breast and prostate cancers, heart disease and other diseases. Med Hypotheses. 2007;68(3):562-4.
  52. Shi M, Wang X, Yamanaka T, Ogita F, Nakatani K, Takeuchi T. Effects of anaerobic exercise and aerobic exercise on biomarkers of oxidative stress. Environ Health Prev Med. 2007 Sep;12(5):202-8.
  53. Epplein M, Franke AA, Cooney RV, et al. Association of plasma micronutrient levels and urinary isoprostane with risk of lung cancer: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev. 2009 Jul;18(7):1962-70.
  54. Rossner P, Jr., Gammon MD, Terry MB, et al. Relationship between urinary 15-F2t-isoprostane and 8-oxodeoxyguanosine levels and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 2006 Apr;15(4):639-44.
  55. Framroze B, Sawant S.The effect of industrial processing of salmon oil on its ability to reduce serum concentrations of oxidized low-density lipoprotein- b2-glycoprotein-I complex in a mouse model. Functional Foods in Health and Disease 2014; 4(10):463-73.
  56. Rainwater DL, Mahaney MC, VandeBerg JL, Wang XL. Vitamin E dietary supplementation significantly affects multiple risk factors for cardiovascular disease in baboons. Am J Clin Nutr. 2007 Sep;86(3):597-603.
  57. Ghafoorunissa, Hemalatha S, Rao MV. Sesame lignans enhance antioxidant activity of vitamin E in lipid peroxidation systems. Mol Cell Biochem. 2004 Jul;262(1-2):195-202.
  58. Malaguarnera M, Vacante M, Avitabile T, Malaguarnera M, Cammalleri L, Motta M. L-Carnitine supplementation reduces oxidized LDL cholesterol in patients with diabetes. Am J Clin Nutr. 2009 Jan;89(1):71-6.
  59. Rogalska J, Brzoska MM, Roszczenko A, Moniuszko-Jakoniuk J. Enhanced zinc consumption prevents cadmium-induced alterations in lipid metabolism in male rats. Chem Biol Interact. 2009 Jan 27;177(2):142-52.
  60. Sano A, Uchida R, Saito M, et al. Beneficial effects of grape seed extract on malondialdehyde-modified LDL. J Nutr Sci Vitaminol (Tokyo). 2007 Apr;53(2):174-82.
  61. Tome-Carneiro J, Gonzalvez M, Larrosa M, et al. Consumption of a grape extract supplement containing resveratrol decreases oxidized LDL and ApoB in patients undergoing primary prevention of cardiovascular disease: a triple-blind, 6-month follow-up, placebo-controlled, randomized trial. Mol Nutr Food Res. 2012 May;56(5):810-21.
  62. Aviram M, Dornfeld L, Kaplan M, et al. Pomegranate juice flavonoids inhibit low-density lipoprotein oxidation and cardiovascular diseases: studies in atherosclerotic mice and in humans. Drugs Exp Clin Res. 2002;28(2-3):49-62. Review.
  63. Fang X, Weintraub NL, Rios CD, et al. Overexpression of human superoxide dismutase inhibits oxidation of low-density lipoprotein by endothelial cells. Circ Res. 1998 Jun 29;82(12):1289-97.
  64. Ahmadvand H, Mabuchi H, Nohara A, Kobayahi J, Kawashiri MA. Effects of coenzyme Q(10) on LDL oxidation in vitro. Acta Med Iran. 2013;51(1):12-8.
  65. Vigna GB, Costantini F, Aldini G, et al. Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokers. Metabolism. 2003 Oct;52(10):1250-7.
  66. Nampoothiri SV, Prathapan A, Cherian OL, Raghu KG, Venugopalan VV, Sundaresan A. In vitro antioxidant and inhibitory potential of Terminalia bellerica and Emblica officinalis fruits against LDL oxidation and key enzymes linked to type 2 diabetes. Food Chem Toxicol. 2011 Jan;49(1):125-31
  67. Available at: http://www.atherotech.com/aboutus/presskit.asp?presskititem=glossary. Accessed March 27, 2015.
  68. Available at: http://www.clevelandheartlab.com/wp-content/uploads/2014/01/oxldl-practitioner-onepager-chl-d007c.pdf. Accessed March 27, 2015.
  69. Available at: http://www.clevelandheartlab.com/wp-content/uploads/2013/04/mpo-physician-one-pager_chl-d006.pdf. Accessed March 27, 2015.
  70. Available at: http://www.clevelandheartlab.com/tests/f2-isoprostanecreatinine-ratio. Accessed March 27, 2015.
  71. Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P. Redox regulation of cell survival. Antioxid Redox Signal. 2008 Aug;10(8):1343-74.
  72. Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacogn Rev. 2010 Jul;4(8):118-26.
  73. Filipovic N, Rosic M, Tanaskovic I, Parodi O, Fotiadis D. Computer simulation and experimental analysis of LDL transport in the arteries. Conf Proc IEEE Eng Med Biol Soc. 2011;2011:195-8.
  74. Singh RB, Mengi SA, Xu YJ, Arneja AS, Dhalla NS. Pathogenesis of atherosclerosis: A multifactorial process. Exp Clin Cardiol. 2002 Spring;7(1):40-53.
  75. Westhorpe CL, Dufour EM, Maisa A, Jaworowski A, Crowe SM, Muller WA. Endothelial cell activation promotes foam cell formation by monocytes following transendothelial migration in an in vitro model. Exp Mol Pathol. 2012 Oct;93(2):220-6.
  76. Sharma G, She ZG, Valenta DT, Stallcup WB, Smith JW. Targeting of macrophage foam cells in atherosclerotic plaque using oligonucleotide-functionalized nanoparticles. Nano Life. 2010 Sep;1 (3-4):207-214.
  77. McLaren JE, Michael DR, Ashlin TG, Ramji DP. Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy. Prog Lipid Res. 2011 Oct;50(4):331-47.
  78. Angelovich TA, Hearps AC, Jaworowski A. Inflammation-induced foam cell formation in chronic inflammatory disease. Immunol Cell Biol. 2015 Mar 10. doi: 10.1038/icb.2015.26.
  79. Ikeshita S, Miyatake Y, Otsuka N, Kasahara M. MICA/B expression in macrophage foam cells infiltrating atherosclerotic plaques. Exp Mol Pathol. 2014 Aug;97(1):171-5.
  80. Francis AA, Pierce GN. An integrated approach for the mechanisms responsible for atherosclerotic plaque regression. Exp Clin Cardiol. 2011 Fall;16(3):77-86.
  81. Tabas I. Macrophage apoptosis in atherosclerosis: consequences on plaque progression and the role of endoplasmic reticulum stress. Antioxid Redox Signal. 2009 Sep;11(9):2333-9.
  82. Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012 Sep;32(9):2045-51.
  83. Galkina E, Ley K. Immune and inflammatory mechanisms of atherosclerosis (*). Annu Rev Immunol. 2009;27:165-97.
  84. Douglas AF, Christopher S, Amankulor N, et al. Extracranial carotid plaque length and parent vessel diameter significantly affect baseline ipsilateral intracranial blood flow. Neurosurgery. 2011 Oct;69(4):767-73; discussion 773.
  85. Murrant CL. Structural and functional limitations of the collateral circulation in peripheral artery disease. J Physiol. 2008 Dec 15;586(Pt 24):5845.
  86. Wootton DM, Ku DN. Fluid mechanics of vascular systems, diseases, and thrombosis. Annu Rev Biomed Eng. 1999;1:299-329.
  87. Yang C, Tang D, Kobayashi S, et al. Cyclic bending contributes to high stress in a human coronary atherosclerotic plaque and rupture risk: In vitro experimental modeling and ex vivo MRI-based computational modeling approach. Mol Cell Biomech. 2008;5(4):259-274.
  88. Paikin JS, Eikelboom JW. Cardiology patient page: aspirin. Circulation. 2012 Mar 13;125(10):e439-42.
  89. Ballantyne CM, Hoogeveen RC, Bang H, et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2004 Feb 24;109(7):837-42.
  90. Ballantyne CM, Hoogeveen RC, Bang H, et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Arch Intern Med. 2005 Nov 28;165(21):2479-84.
  91. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997 Apr 3;336(14):973-9.
  92. Ndrepepa G, Kastrati A, Braun S, et al. N-terminal probrain natriuretic peptide and C-reactive protein in stable coronary heart disease. Am J Med. 2006 Apr;119(4):355.e1-8.
  93. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008 Nov 20;359(21):2195-207.

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