Life Extension Magazine April 2009
As We See It
Dietary Supplements Under Attack
By William Faloon
Life Extension Magazine April 2009
As We See It
By William Faloon
A Hidden Cause of Heart Attack and Stroke
Even when all conventional risk factors are controlled, the progressive decline of nitric oxide in the arterial wall (the endothelium) too often leads to coronary heart attack and stroke.68-75
Seven years ago, Life Extension researchers identified a critical compound (tetrahydrobiopterin) that is an essential cofactor for the enzyme that synthesizes nitric oxide in the endothelium.76 We spent several hundred thousand dollars trying to develop an affordable way to manufacture this compound as it offered tremendous promise for eradicating atherosclerosis.
We failed to find an affordable way to make tetrahydrobiopterin. The good news is that nutrients that suppress peroxynitrite (like gamma tocopherol and pomegranate) increase endothelial nitric oxide by blocking the oxidation of tetrahydrobiopterin.77,78
Indeed, clinical studies show that supplemental gamma tocopherol enhances platelet endothelial nitric oxide synthase activity.52,53 Furthermore, a diet high in gamma tocopherol-rich walnuts improves endothelium-dependent vasodilation in those with high cholesterol.63
By administering only alpha tocopherol as was done in the flawed study, one would expect gamma tocopherol to be suppressed, peroxynitrite levels to increase, and precious tetrahydrobiopterin to be oxidized, thus depriving the endothelium of the nitric oxide it needs to protect against heart attack and stroke. Is it any wonder that this study failed to show vascular disease reduction in those given only alpha (but not gamma) tocopherol?
Failing to Account For All Vascular Risk Factors
Numerous independent risk factors are associated with the development of atherosclerosis and subsequent heart attack and stroke risk. A major flaw in this study was expecting low-dose vitamin C and/or E to somehow overcome all of these underlying causes of artery disease.
We know it is impossible for vitamins C and E to overcome these many risk factors, but this did not stop the media from recommending that Americans discard their supplements.
The following represents a succinct list of documented vascular disease risk factors:
The basis for doing this study, as outlined by the study’s authors, was to use vitamins C and/or E to:
As one can clearly see on the previous page, there are 17 documented cardiovascular risk factors. Yet only three of these risk factors are what formed the basis for conducting this low-dose vitamin C and/or E clinical trial. The three most important risk factors the authors of the flawed study expected to favorably influence with vitamins C and E were:
For every one mechanism the study’s authors proposed might enable low-dose vitamin C and/or synthetic vitamin E to work, there are five additional risk factors that would not be corrected. For instance, vitamins C and E in these low doses are not going to reduce C-reactive protein,86 homocysteine, fibrinogen, or glucose.87 Vitamins C and E in any dose are not going to increase testosterone, decrease estrogen, or provide cardioprotective EPA/DHA and vitamin D.
On the contrary, as we have already shown, by giving only alpha but not gamma tocopherol, one might expect increased LDL oxidation and impaired endothelial function. That’s because alpha tocopherol displaces gamma tocopherol in the body. Gamma tocopherol suppresses the peroxynitrite radical that oxidizes both LDL protein and the tetrahydrobiopterin that is needed to produce endothelial nitric oxide.
As far as platelet activity and thrombotic potential (abnormal clotting inside a blood vessel) are concerned, gamma tocopherol is significantly more potent than alpha tocopherol in inhibiting platelet aggregation that can lead to a heart attack or stroke.52,53 By displacing gamma tocopherol, the alpha tocopherol used alone in this study may have increased abnormal platelet aggregation risk.
From everything we know today, this study was designed to fail. Not only did it not correct for the major causes of vascular disease, but it may have exacerbated some of the more dangerous ones.
None of What I Wrote So Far May Really Matter
You have just learned why low-dose vitamin C and/or E supplementation would not be expected to reduce heart attack and stroke risk.
I have saved the biggest shocker for last. It turns out that a significant number of the study subjects (who were all medical doctors) who were supposed to take the vitamin C and/or E supplements did not take their pills. Yet when the calculations for heart attack or stroke incidence were made, those who took as little as 66% of their low-dose vitamin C and/or E supplements were counted as having taken the entire dose.
At the end of the study, 28% of the study subjects admitted they had not even taken 66% of their low-dose vitamin C and/or E supplements.
Even more troubling is the method used to track who was really taking their supplements. Participants were asked to remember and track supplement usage for over eight years’ time without any verification of actual pill counts, compliance by plasma antioxidant analysis, or in vivo surrogate markers of oxidative stress. Relying upon participants’ memory and recollection over a lengthy time period of many years is a rather pathetic way of ensuring adherence, and renders the authors’ so-called “sensitivity analysis” meaningless.
The lack of adherence, i.e., the fact that a significant percentage of the study participants were not even taking their vitamins, may be the most significant flaw to this study. No one in the mainstream media bothered to report this, or any of the other flaws that jumped out at us.
Instead, the media’s message was don’t waste your money on vitamin C or E pills. Many supplement users who are taking the right form and dose of their vitamin C and E nutrients may believe the media’s biased reporting.
Shocking Deficiencies of Vitamin E
The media used this horrific-ally flawed study as a basis to steer Americans away from vitamin C and E supplements. It’s as if all of the previous positive published studies disappeared overnight.
What was omitted is the fact that 92% of American men and 98% of American women do not consume the recommended dietary allowance of vitamin E in their diet. The federal government says Americans need 15 milligrams per day of vitamin E, yet even this minute amount is not found in the diets of the vast majority of people.88
This means that most Americans require a vitamin E supplement to avoid a chronic deficiency, but this important fact was conveniently left out of the news stories.
Conventional medicine says that severe vitamin E deficiency results mainly in neuro-logical symptoms such as impaired balance and coordination and muscle weakness. These neurological symptoms do not develop for 10-20 years, as it takes time for free radicals to inflict nerve damage in the absence of sufficient vitamin E. The reality is that chronic vitamin E deficiency adversely impacts virtually every cell of the body.89-94
A Media Coup for Pharmaceutical Companies
The optimal moment of the year to get your message to the masses is the second week of November. This is a time in between holidays, when winter is setting in, and few people are on vacation. The television networks consider this their most important “sweeps week” as it provides the most accurate measurement of their ratings.
The timing of the release of this horrendously flawed vitamin C and E study could not have been more perfect for pharmaceutical interests. It came out less than one week after the November elections, when the media was primed to sensationalize any story that would attract viewers for their all important “sweeps week.”
On the very same day the media launched its attack on vitamins C and E, the same news sources reported that very high doses of the statin drug Crestor® reduced heart attack rates by 54% in healthy people who had high C-reactive protein levels.95 Just think, uneducated consumers read on the same day that vitamins C and E are worthless and an expensive statin drug performs miracles.
Financial analysts predict a windfall for the makers of Crestor® based on this widely distributed report. In retrospect, conducting a study only on people with high C-reactive protein (but not particularly high LDL) was a brilliant marketing strategy. It had a high probability of a successful outcome, and if the study failed, Crestor® was never approved to lower C-reactive protein or be used in this population group, so the pharmaceutical company had nothing to lose.
We at Life Extension have long warned about the vascular dangers of elevated C-reactive protein and even recommended statin drugs if natural approaches fail to reduce C-reactive protein. We don’t believe most people have to purchase expensive brand name drugs like Crestor®, as generic simvastatin (name brand Zocor®) or pravastatin (name brand Pravachol®) can provide similar benefit at a fraction of the price.
Media Also Attacks Vitamin D
Not content to bash only vitamins C and E, the media the very next day in November 2008 ran a headline story stating that “Supplements don’t reduce breast cancer risk.” This story was based on a study of women who received only 400 IU a day of supplemental vitamin D.96
As has been reported for years in this and other health publications, 400 IU a day of vitamin D is clearly inadequate.97 To reduce breast cancer risk by around 50%, a daily dose of 1,000 IU and higher is required. The major flaw in this study is that participants in the active and placebo group were allowed to take vitamin D outside the study, which rendered the findings meaningless even if the proper dose had been given.
The fact that the media made this study headline news is regrettable because only about 20% of the study population achieved a 25-hydroxyvitamin D blood result at the minimum level required to prevent breast cancer (approximately 30 ng/mL or higher). In other words, most participants in the active or placebo group failed to achieve even the minimal blood concentrations of vitamin D that other studies document are needed to protect against breast cancer.98 So all this study did was help confirm what vitamin D experts have been saying for over five years now, i.e., a minimum of 800 IU to 1,000 IU of vitamin D a day is required… not the 400 IU used in this study.
Don’t Be a Victim of This Flawed Propaganda
It is in the economic interests of drug companies to steer Americans away from healthier lifestyles and dietary supplements. As more Americans fall ill to degenerative disease, drug company profits increase exponentially.
Enormous amounts of pharmaceutical dollars are spent influencing Congress, the FDA, and other federal agencies. The result is the promulgation of policies that cause Americans to be deprived of effective, low-cost means of protecting themselves against age-related disease.
As a member of the Life Extension Foundation, you gain access to scientific information that is interpreted in the context of what health-conscious people are really doing to protect themselves against age-related diseases. You also learn how this information is distorted by the government, drug companies, and the media to discourage the public from following healthier lifestyles.
1. Gey KF, Puska P, Jordan P, Moser UK. Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr. 1991 Jan;53(1 Suppl):326S-34S.
2. Gey KF, Moser UK, Jordan P, et al. Increased risk of cardiovascular disease at suboptimal plasma concentrations of essential antioxidants: an epidemiological update with special attention to carotene and vitamin C. Am J Clin Nutr. 1993 May;57(5 Suppl):787S-97S.
3. Knekt P, Reunanen A, Jarvinen R, et al. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol. 1994 Jun 15;139(12):1180-9.
4. Losonczy KG, Harris TB, Havlik RJ. Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemio-logic Studies of the Elderly. Am J Clin Nutr. 1996 Aug;64(2):190-6.
5. Nyyssonen K, Parviainen MT, Salonen R, Tuomilehto J, Salonen JT. Vitamin C deficiency and risk of myocardial infarction: prospective population study of men from eastern Finland. BMJ. 1997 Mar 1;314(7081):634-8.
6. Kushi LH, Folsom AR, Prineas RJ, et al. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med. 1996 May 2;334(18):1156-62.
7. Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidemiology. 1992 May;3(3):194-202.
8. Sesso HD, Buring JE, Christen WG, et al. Vitamins E and C in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2008 Nov 12;300(18):2123-33.
9. Gorelik S, Lapidot T, Shaham I, et al. Lipid peroxidation and coupled vitamin oxidation in simulated and human gastric fluid inhibited by dietary polyphenols: health implications. J Agric Food Chem. 2005 May 4;53(9):3397-402.
10. Kanner J, Lapidot T. The stomach as a bioreactor: dietary lipid peroxidation in the gastric fluid and the effects of plant-derived antioxidants. Free Radic Biol Med. 2001 Dec 1;31(11):1388-95.
11. Devaraj S, Tang R, Adams-Huet B, et al. Effect of high-dose alpha-tocopherol supplementation on biomarkers of oxidative stress and inflammation and carotid atherosclerosis in patients with coronary artery disease. Am J Clin Nutr. 2007 Nov;86(5):1392-8.
12. Kiyose C, Muramatsu R, Kameyama Y, Ueda T, Igarashi O. Biodiscrimination of alpha-tocopherol stereoisomers in humans after oral administration. Am J Clin Nutr. 1997 Mar;65(3):785-9.
13. Wilburn EE, Mahan DC, Hill DA, Shipp TE, Yang H. An evaluation of natural (RRR-alpha-tocopheryl acetate) and synthetic (all-rac-alpha-tocopheryl acetate) vitamin E fortification in the diet or drinking water of weanling pigs. J Anim Sci. 2008 Mar;86(3):584-91.
14. Hayton SM, Kriss A, Wade A, Muller DP. The effects of different levels of all-rac- and RRR-alpha-tocopheryl acetate (vitamin E) on visual function in rats. Clin Neurophysiol. 2003 Nov;114(11):2124-31.
15. Hoppe PP, Krennrich G. Bioavailability and potency of natural-source and all-racemic alpha-tocopherol in the human: a dispute. Eur J Nutr. 2000 Oct;39(5):183-93.
16. Lodge JK. Vitamin E bioavailability in humans. J Plant Physiol. 2005 Jul;162(7):790-6.
17. Burton GW, Traber MG, Acuff RV, et al. Human plasma and tissue alpha-tocopherol concentrations in response to supplementation with deuterated natural and synthetic vitamin E. Am J Clin Nutr. 1998 Apr;67(4):669-84.
18. Traber MG. Utilization of vitamin E. Biofactors. 1999;10(2-3):115-20.
19. Blatt DH, Leonard SW, Traber MG. Vitamin E kinetics and the function of tocopherol regulatory proteins. Nutrition. 2001 Oct;17(10):799-805.
20. Rigotti A. Absorption, transport, and tissue delivery of vitamin E. Mol Aspects Med. 2007 Oct;28(5-6):423-36.
21. Blatt DH, Pryor WA, Mata JE, Rodriguez-Proteau R. Re-evaluation of the relative potency of synthetic and natural alpha-tocopherol: experimental and clinical observations. J Nutr Biochem. 2004 Jul;15(7):380-95.
22. Mustacich DJ, Bruno RS, Traber MG. Vitamin E. Vitam Horm. 2007;76:1-21.
23. Manor D, Morley S. The alpha-tocopherol transfer protein. Vitam Horm. 2007;76:45-65.
24. Morley S, Cecchini M, Zhang W, et al. Mechanisms of ligand transfer by the hepatic tocopherol transfer protein. J Biol Chem. 2008 Jun 27;283(26):17797-804.
25. Traber MG. Vitamin E regulatory mechanisms. Annu Rev Nutr. 2007;27:347-62.
26. Nappo F, De RN, Marfella R, et al. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. JAMA. 1999 Jun 9;281(22):2113-8.
27. Valkonen MM, Kuusi T. Vitamin C prevents the acute atherogenic effects of passive smoking. Free Radic Biol Med. 2000 Feb 1;28(3):428-36.
28. Jeserich M, Schindler T, Olschewski M, et al. Vitamin C improves endothelial function of epicardial coronary arteries in patients with hypercholesterolaemia or essential hypertension--assessed by cold pressor testing. Eur Heart J. 1999 Nov;20(22):1676-80.
29. Wilkinson IB, Megson IL, MacCallum H, et al. Oral vitamin C reduces arterial stiffness and platelet aggregation in humans. J Cardiovasc Pharmacol. 1999 Nov;34(5):690-3.
30. Jablonski KL, Seals DR, Eskurza I, Monahan KD, Donato AJ. High-dose ascorbic acid infusion abolishes chronic vasoconstriction and restores resting leg blood flow in healthy older men. J Appl Physiol. 2007 Nov;103(5):1715-21.
31. Hernandez-Guerra M, Garcia-Pagan JC, Turnes J, et al. Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Hepatology. 2006 Mar;43(3):485-91.
32. Knekt P, Ritz J, Pereira MA, et al. Antioxidant vitamins and coronary heart disease risk: a pooled analysis of 9 cohorts. Am J Clin Nutr. 2004 Dec;80(6):1508-20.
33. Rath M, Pauling L. Immunological evidence for the accumulation of lipoprotein(a) in the atherosclerotic lesion of the hypoascorbemic guinea pig. Proc Natl Acad Sci USA. 1990 Dec;87(23):9388-90.
34. Pauling L. Are recommended daily allowances for vitamin C adequate? Proc Natl Acad Sci USA. 1974 Nov;71(11):4442-6.
35. Krumdieck C, Butterworth CE, Jr. Ascorbate--cholesterol--lecithin interactions: factors of potential importance in the pathogenesis of atherosclerosis. Am J Clin Nutr. 1974 Aug;27(8):866-76.
36. Ginter E. Cholesterol: vitamin C controls its transformation to bile acids. Science. 1973 Feb 16;179(74):702-4.
37. Ferroni F, Maccaglia A, Pietraforte D, Turco L, Minetti M. Phenolic antioxidants and the protection of low density lipoprotein from peroxynitrite-mediated oxidations at physiologic CO2. J Agric Food Chem. 2004 May 19;52(10):2866-74
38. Helzlsouer KJ, Huang HY, Alberg AJ, et al. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000 Dec 20;92(24):2018-23.
39. Christen S, Woodall AA, Shigenaga MK, et al. gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications. Proc Natl Acad Sci USA. 1997 Apr 1;94(7):3217-22.
40. Devaraj S, Leonard S, Traber MG, Jialal I. Gamma-tocopherol supplementation alone and in combination with alpha-tocopherol alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome. Free Radic Biol Med. 2008 Mar 15;44(6):1203-8.
41. Reiter E, Jiang Q, Christen S. Anti-inflammatory properties of alpha- and gamma-tocopherol. Mol Aspects Med. 2007 Oct;28(5-6):668-91.
42. Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN. gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Proc Natl Acad Sci USA. 2000 Oct 10;97(21):11494-9.
43. Handelman GJ, Machlin LJ, Fitch K, Weiter JJ, Dratz EA. Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans. J Nutr. 1985 Jun;115(6):807-13.
44. Wolf G. Gamma-Tocopherol: an efficient protector of lipids against nitric oxide-initiated peroxidative damage. Nutr Rev. 1997 Oct;55(10):376-8.
45. Botti H, Batthyány C, Trostchansky A, Radi R, Freeman BA, Rubbo H. Peroxynitrite-mediated alpha-tocopherol oxidation in low-density lipoprotein: a mechanistic approach. Free Radic Biol Med. 2004 Jan 15;36(2):152-62.
46. Yla-Herttuala S, Palinski W, Rosenfeld ME, et al. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989 Oct;84(4):1086-95.
47. Steinberg D, Carew TE, Fielding C, et al. Lipoproteins and the pathogenesis of atherosclerosis. Circulation. 1989 Sep;80(3):719-23.
48. Torres-Rasgado E, Fouret G, Carbonneau MA, Leger CL. Peroxynitrite mild nitration of albumin and LDL-albumin complex naturally present in plasma and tyrosine nitration rate-albumin impairs LDL nitration. Free Radic Res. 2007 Mar;41(3):367-75.
49. Uno M, Kitazato KT, Suzue A, Itabe H, Hao L, Nagahiro S. Contribution of an imbalance between oxidant-antioxidant systems to plaque vulnerability in patients with carotid artery stenosis. J Neurosurg. 2005 Sep;103(3):518-25.
50. Botti H, Trostchansky A, Batthyány C, Rubbo H. Reactivity of peroxynitrite and nitric oxide with LDL. IUBMB Life. 2005 Jun;57(6):407-12.
51. Rubbo H, Batthyany C, Radi R. Nitric oxide-oxygen radicals interactions in atherosclerosis. Biol Res. 2000;33(2):167-75.
52. Li D, Saldeen T, Romeo F, Mehta JL. Relative Effects of alpha- and gamma-Tocopherol on Low-Density Lipoprotein Oxidation and Superoxide Dismutase and Nitric Oxide Synthase Activity and Protein Expression in Rats. J Cardiovasc Pharmacol Ther. 1999 Oct;4(4):219-26.
53. Saldeen T, Li D, Mehta JL. Differential effects of alpha- and gamma-tocopherol on low-density lipoprotein oxidation, superoxide activity, platelet aggregation and arterial thrombogenesis. J Am Coll Cardiol. 1999 Oct;34(4):1208-15.
54. Mikunis RI, Serkova VK, Shirkova TA. Lipid metabolism and oxidation-reduction properties of blood in patients with arteriosclerotic myocardiosclerosis during treatment with lipoic acid. Vrach Delo. 1976 Mar;(3):39-42.
55. Nickander KK, McPhee BR, Low PA, Tritschler H. Alpha-lipoic acid: antioxidant potency against lipid peroxidation of neural tissues in vitro and implications for diabetic neuropathy. Free Radic Biol Med. 1996;21(5):631-9.
56. Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med. 1997;22(1-2):359-78.
57. Arivazhagan P, Shila S, Kumaran S, Panneerselvam C. Effect of DL-alpha-lipoic acid on the status of lipid peroxidation and antioxidant enzymes in various brain regions of aged rats. Exp Gerontol. 2002 Jun;37(6):803-11.
58. Arivazhagan P, Thilakavathy T, Ramanathan K, Kumaran S, Panneerselvam C. Effect of DL-alpha-lipoic acid on the status of lipid peroxidation and protein oxidation in various brain regions of aged rats. J Nutr Biochem. 2002 Oct;13(10):619-24.
59. Ozgova S, Hermanek J, Gut I. Different antioxidant effects of polyphenols on lipid peroxidation and hydroxyl radicals in the NADPH-, Fe-ascorbate- and Fe-microsomal systems. Biochem Pharmacol. 2003 Oct 1;66(7):1127-37.
60. Thirunavukkarasu V, Anuradha CV. Influence of alpha-lipoic acid on lipid peroxidation and antioxidant defence system in blood of insulin-resistant rats. Diabetes Obes Metab. 2004 May;6(3):200-7.
61. Thirunavukkarasu V, Anitha Nandhini AT, Anuradha CV. Cardiac lipids and antioxidant status in high fructose rats and the effect of alpha-lipoic acid. Nutr Metab Cardiovasc Dis. 2004 Dec;14(6):351-7.
62. Singh I, Turner AH, Sinclair AJ, Li D, Hawley JA. Effects of gamma-tocopherol supplementation on thrombotic risk factors. Asia Pac J Clin Nutr. 2007;16(3):422-8.
63. Ros E, Nunez I, Perez-Heras A, et al. A walnut diet improves endothelial function in hypercholesterolemic subjects: a randomized crossover trial. Circulation. 2004 Apr 6;109(13):1609-14.
64. Dietrich M, Traber MG, Jacques PF, Cross CE, Hu Y, Block G. Does gamma-tocopherol play a role in the primary prevention of heart disease and cancer? A review. J Am Coll Nutr. 2006 Aug;25(4):292-9.
65. McLaughlin PJ, Weihrauch JL. Vitamin E content of foods. J Am Diet Assoc. 1979 Dec;75(6):647-65.
66. Tanaka Y, Wood LA, Cooney RV. Enhancement of intracellular gamma-tocopherol levels in cytokine-stimulated C3H 10T1/2 fibroblasts: relation to NO synthesis, isoprostane formation, and tocopherol oxidation. BMC Chem Biol. 2007;72.
67. Gao R, Stone WL, Huang T, Papas AM, Qui M. The uptake of tocopherols by RAW 264.7 macrophages. Nutr J. 2002 Oct 15;12.
68. Giannotti G, Landmesser U. Endothelial dysfunction as an early sign of atherosclerosis. Herz. 2007 Oct;32(7):568-72.
69. Pesic S, Radenkovic M, Grbovic L. Endothelial dysfunction: mechanisms of development and therapeutic options. Med Pregl. 2006 Jul-Aug;59(7-8):335-41.
70. Halcox JP, Schenke WH, Zalos G, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002 Aug 6;106(6):653-8.
71. Targonski PV, Bonetti PO, Pumper GM, et al. Coronary endothelial dysfunction is associated with an increased risk of cerebrovascular events. Circulation. 2003 Jun 10;107(22):2805-9.
72. von Mering GO, Arant CB, Wessel TR, et al. Abnormal coronary vasomotion as a prognostic indicator of cardiovascular events in women: results from the National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation. 2004 Feb 17;109(6):722-5.
73. Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001 Nov 27;104(22):2673-8.
74. Chan SY, Mancini GB, Kuramoto L, et al. The prognostic importance of endothelial dysfunction and carotid atheroma burden in patients with coronary artery disease. J Am Coll Cardiol. 2003 Sep 17;42(6):1037-43.
75. Brevetti G, Silvestro A, Schiano V, Chiariello M. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation. 2003 Oct 28;108(17):2093-8.
76. Ali ZA, Bursill CA, Douglas G, et al. CCR2-mediated antiinflammatory effects of endothelial tetrahydrobiopterin inhibit vascular injury-induced accelerated atherosclerosis. Circulation. 2008 Sep 30;118(14 Suppl):S71-7.
77. McCarty MF. Gamma-tocopherol may promote effective no synthase function by protecting tetrahydrobiopterin from peroxynitrite. Med Hypotheses. 2007;69(6):1367-70.
78. de Nigris F, Balestrieri ML, Williams-Ignarro S, et al. The influence of pomegranate fruit extract in comparison to regular pomegranate juice and seed oil on nitric oxide and arterial function in obese Zucker rats. Nitric Oxide. 2007 Aug;17(1):50-4.
79. Stocker R, Bowry VW, Frei B. Ubiquinol-10 protects human low density lipoprotein more efficiently against lipid peroxidation than does alpha-tocopherol. Proc Natl Acad Sci USA. 1991 Mar 1;88(5):1646-50.
80. Frei B, Kim MC, Ames BN. Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Proc Natl Acad Sci USA. 1990 Jun;87(12):4879-83.
81. Thomas SR, Neuzil J, Stocker R. Inhibition of LDL oxidation by ubiquinol-10. A protective mechanism for coenzyme Q in atherogenesis? Mol Aspects Med. 1997;18(Suppl):S85-103.
82. Mohr D, Bowry VW, Stocker R. Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation. Biochim Biophys Acta. 1992 Jun 26;1126(3):247-54.
83. Kontush A, Hubner C, Finckh B, Kohlschutter A, Beisiegel U. Antioxidative activity of ubiquinol-10 at physiologic concentrations in human low density lipoprotein. Biochim Biophys Acta. 1995 Sep 14;1258(2):177-87.
84. Bowry VW, Mohr D, Cleary J, Stocker R. Prevention of tocopherol-mediated peroxidation in ubiquinol-10-free human low density lipoprotein. J Biol Chem. 1995 Mar 17;270(11):5756-63.
85. Tribble DL, van den Berg JJ, Motchnik PA, et al. Oxidative susceptibility of low density lipoprotein subfractions is related to their ubiquinol-10 and alpha-tocopherol content. Proc Natl Acad Sci USA. 1994 Feb 1;91(3):1183-7.
86. Block G, Jensen CD, Dalvi TB, et al. Vitamin C treatment reduces elevated C-reactive protein. Free Radic Biol Med. 2009 Jan 1;46(1):70-7.
87. Afkhami-Ardekani M, Shojaoddiny-Ardekani A. Effect of vitamin C on blood glucose, serum lipids & serum insulin in type 2 diabetes patients. Indian J Med Res. 2007 Nov;126(5):471-4.
88. Maras JE, Bermudez OI, Qiao N, et al. Intake of alpha-tocopherol is limited among US adults. J Am Diet Assoc. 2004 Apr;104(4):567-75.
89. Puri V, Chaudhry N, Tatke M, Prakash V. Isolated vitamin E deficiency with demyelinating neuropathy. Muscle Nerve. 2005 Aug;32(2):230-5.
90. Schuelke M, Finckh B, Sistermans EA, et al. Ataxia with vitamin E deficiency: biochemical effects of malcompliance with vitamin E therapy. Neurology. 2000 Nov 28;55(10):1584-6.
91. Tanyel MC, Mancano LD. Neurologic findings in vitamin E deficiency. Am Fam Physician. 1997 Jan;55(1):197-201.
92. Sokol RJ. Vitamin E deficiency and neurologic disease. Annu Rev Nutr. 1988;8:351-73.
93. Satya-Murti S, Howard L, Krohel G, Wolf B. The spectrum of neurologic disorder from vitamin E deficiency. Neurology. 1986 Jul;36(7):917-21.
94. Laplante P, Vanasse M, Michaud J, Geoffroy G, Brochu P. A progressive neurological syndrome associated with an isolated vitamin E deficiency. Can J Neurol Sci. 1984 Nov;11(4 Suppl):561-4.
95. Available at: http://www.medpagetoday.com/MeetingCoverage/AHA/11684. Accessed January 20, 2009.
96. Chlebowski RT, Johnson KC, Kooperberg C, et al. Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst. 2008 Nov 19;100(22):1581-91.
97. Garland CF, Garland FC, Gorham ED, et al. The role of vitamin D in cancer prevention. Am J Public Health. 2006 Feb;96(2):252-61.
98. Neuhouser ML, Sorensen B, Hollis BW, et al. Vitamin D insufficiency in a multiethnic cohort of breast cancer survivors. Am J Clin Nutr. 2008 Jul;88(1):133-9.
99. Kemper KJ, Hood KL. Does pharmaceutical advertising affect journal publication about dietary supplements? BMC Complement Altern Med. 2008;811.