Low-density lipoproteins have long been the measure by which risk of cardiovascular disease is determined. Recent studies also support the role of the secondary markers homocysteine, triglycerides, lipoprotein(a) and C-reactive protein as being equally valuable indicators. Conrad Earnest, PhD, FACSM, investigates.
Several years ago, a prominent scientist presented data at an American Heart Association medical conference on statin medications showing that a large cohort of subjects at high risk for cardiovascular disease (CVD) exhibited a one-third reduced risk for infarction and stroke. Puzzlingly, those on statin drugs—commonly prescribed to reduce cholesterol—who also took antioxidants fared less well. In a news conference, the investigator remarked that the study ?clearly demonstrates that treatment with antioxidant vitamins confers no cardiovascular benefit, and this issue should now be laid to rest!?
This opinion is not shared by others.1 However, it does create confusion regarding vitamin use. Should we ignore strong data suggesting a CVD benefit? Should we draw conclusions based on short-term studies—those lasting less than five years? Are we inadvertently assigning vitamins the role of drugs, rather than that of prophylactic measures to reduce disease incidence?
Overall, advocacy for supplements use has merit, given that several studies show an association between reduced disease risk and antioxidant-rich foods and supplements.2,3 This follows from the real issue—that most people maintain or endure poor-quality diets even when knowing the ?rules? of good nutrition.
A classic example for supplements advocacy is the 85,000-subject Nurses? Health Study showing that the risk of coronary disease was lowest in those ingesting a high level of vitamin E—an achievement possible only by supplementation.4 The Health Professionals Follow-up Study of 39,000 subjects and the Cambridge Heart Antioxidant Study describe similar patterns.2,5
Perhaps a key to appreciating the prophylactic utility of supplements is the observation that CVD is a slow process, taking decades to manifest itself. Therefore, three objectives should be kept in mind when considering supplementation.
First, research should be based on trial length and the external habits of the participants. The 29,000-subject Alpha-tocopherol, beta-carotene Cancer Prevention Study examined male smokers, showing vitamin E and beta-carotene supplementation to be unexpectedly associated with a non-significant increase in mortality from lung cancer and ischemic heart disease.6 Bad news for smokers—but what about the rest of us?
Second, examine the consistency among findings of observational and epidemiological studies and randomised trials. Observationally, diets rich in antioxidants are also lower in saturated fat and cholesterol and higher in fibre and micronutrient distribution, because foods rich in vitamins C and E and beta-carotene also contain minerals, flavonoids, phytochemicals and carotenoids other than beta-carotene.7
Lastly, many trials in the literature are less than five years in length. Therefore, we are asked to consider the paradox that CVD takes two to three decades to materialise, yet the medical expectation of supplementation assumes we can reverse this disease process in less than five years.
Although cholesterol is often the primary focus of many articles related to CVD, this article is specifically related to secondary risk factors for CVD that may be affected by supplementation: homocysteine, triglycerides, lipoprotein(a) and C?reactive protein (CRP).
Homocysteine is a sulphur-containing amino acid recognised as a risk factor for CVD. Normal fasting homocysteine levels range from 5?15micromol/L, with moderate (16?30micromol/L), intermediate (31?100micromol/L), and severe homocysteinaemia (>100micromol/L) concentrations showing increasing risk.8 However, these are broad guidelines and some labs may use more stringent criteria. A number of studies have shown an inverse relationship between homocysteine and concentrations of folic acid, vitamin B6 and vitamin B12 in the blood.9,10
Folic acid supplements in doses between 0.2mg and 15mg/day can lower plasma homocysteine concentrations without apparent toxicity.11,12 On the basis of a meta-analysis of 12 clinical studies, it has been estimated that between 0.5mg and 5.7mg/day folic acid can reduce homocysteine levels by 25 per cent.13
Vitamin B6 also appears to play a role in the control of homocysteine. Both open-label and placebo-controlled trials reveal that doses of 50?250mg/day acutely reduce homocysteine concentrations by 25 per cent after a methionine-loading test protocol.14,15 An oral methionine loading test is often used to determine drug or nutrient interventions, because from 20 to 40 per cent of the population have been estimated to have normal fasting homocysteine levels that are raised only after an oral methionine loading test. Thus, the test itself examines the rate of homocysteine increase in the blood accompanying the ingestion of the homocysteine precursor, methionine.
Combination agents including folic acid and vitamins B6 and B12 can also be effective. For example, a placebo-controlled study using a combination of multiple agents including folic acid (0.65mg/day), vitamin B6 (10mg/day) and vitamin B12 (0.4mg/day) reduced homocysteine in patients with hyperhomocysteinaemia.18
Interestingly, observational and clinical trials show that though current dietary recommendations are easily achievable via food, additional supplementation may be needed to gain the most benefit.19,20 This is further supported by one trial showing that increasing vitamin intake from food failed to maintain normal homocysteine concentrations attained previously by vitamin supplementation.21
Other vitamins also may influence homocysteine, including a daily food intake of vitamin B2 (riboflavin), which can function as a co-factor for MTHFR,22 a regulatory enzyme in homocysteine metabolism.23 However, pharmacological doses of nicotinic acid (3,000mg/day) may increase homocysteine.24 Lycopene has also been shown to be effective independently and in combination, as several studies show a reduction in homocysteine with increasing lycopene concentrations.16,17,25 Similar responses have been observed with soy, because soy is a rich source of vitamin B6 and folate.26,27,28
In addition, some studies have shown that betaine may be effective if first-line recommendations do not show a benefit.29 For example, if repeat analysis of homocysteine after one month shows treatment is ineffective, the administration of 6g betaine may show some benefit because betaine is an intermediate metabolite from choline, which aids in the regulatory enzyme pathway of converting homocysteine to methionine.30
Triglycerides are the form in which most fat exists in food and in the body. In plasma, triglycerides are derived from fats eaten in foods or made from other energy sources like carbohydrates. Excess triglycerides in the blood is called hypertriglyceridaemia and is linked to CVD. The National Cholesterol Education Program guidelines for triglycerides are:
- Normal (
- Borderline-high (150?199mg/dL)
- High (200?499mg/dL)
- Very high (>500mg/dL)
For individuals with severe lipoprotein disorders such as familial hypercholesterolaemia, for whom diet therapy is helpful but not adequate, the use of medications is now indicated.
Niacin (vitamin B3), is one such intervention. It?s a nutrient that has traditionally claimed fame for its ability to increase circulating HDL cholesterol. However, niacin also has positive effects on triglyceride concentrations, one of the most positive being its influence on raising HDL-C.1,31,32
However, a blanket recommendation of niacin is complicated by the potential discomfort of flushing. Hence, a stepwise approach to managing elevated triglycerides should start with classic interventions such as weight reduction, alcohol and smoking reduction/cessation, and physical exercise as first-line actions.33
When necessary, supplementation provides a low-cost alternative to drug therapy. 29,30 One of the mechanisms of action for niacin?s effect is its potential for reducing free fatty acids in the liver and the synthesis of very low-density lipoproteins. 34 In this regard, early research has shown niacin to reduce triglycerides by 20 to 36 per cent, depending on the population studied. 35,36 For those resigned to medications such as statins, niacin may provide additional benefits on lipid levels. 37
Some caution may be advised because an elevation of selected liver enzymes has been observed in one combination study.32
N-3 fish oil is another supplement that affects triglycerides.38 In a recent trial, 24 men with high abdominal (aka, visceral) obesity were randomly assigned to receive either fish oil capsules (4g/day, consisting of 45 per cent EPA and 39 per cent DHA) or a matching placebo (corn oil, 4g/day) for six weeks. At the end of this study, fish oil was shown to lower triglycerides by 18 per cent compared with the placebo.39 Similar effects have also been noted in women.
In a slightly larger trial, 31 women were assigned to one of four groups, equalized on the basis of their fasting triglyceride concentrations. The groups received supplements providing (1) 4g EPA+DHA (4:0, EPA+DHA:GLA; control group), (2) 4g EPA+DHA plus 1g GLA (4:1), (3) 2g GLA (4:2), or (4) 4g GLA (4:4) daily for 28 days. Triglycerides were significantly lower in groups one, two and three. LDL cholesterol also decreased significantly, by 11.3 per cent, in the third group.40 Similar findings have also been demonstrated in patients who are genetically predisposed toward atherogenesis.41
An interesting avenue for delivery is eggs. For example, when 70g/kg of cod liver oil, canola oil or linseed oil are added to a commercial control diet in hens, the n-3 profile is increased from 1.2 per cent in the egg yolk to 6.3, 4.6, and 7.8 per cent, respectively. Feeding flaxseed increases linolenic acid in the egg yolk by about 30-fold, and DHA increases it nearly fourfold.
When individuals were fed four enriched eggs a day for four weeks, total cholesterol levels and low-density lipoprotein cholesterol (LDL-C) do not increase—a common warning against egg consumption—yet triglyceride levels significantly decreased.42 Although not confirmed by all studies, this may be an issue of dose dependency as higher n-3 in the egg or a greater egg intake is needed before an effect is observed.43
Garlic should also be given consideration for triglyceride reduction. Early studies in rabbits were the first to show that garlic may be useful in reducing cholesterol and triglycerides.44 These observations were followed by human studies of those at risk for CVD.45 Though most studies are small, more contemporary findings seem to confirm the same findings.46,47 Not all studies confirm these effects48,49 and it is not uncommon to cite garlic body odour as a cause of patients stopping garlic therapy.48
Overall, however, results of a meta-analysis show about a 12 per cent reduction with 600?800mg/day garlic.50 Yet, even meta-analyses can yield conflicting results and may be inadvertently biased if the sample sizes examined are small.51
The potential for combining garlic and n-3 fatty acids also appears to have a synergistic effect when taken together.52 In one short one-month trial, a combination of fish oil (1,800mg EPA plus 1,200mg DHA) and 1,200mg garlic powder taken daily resulted in an 11 per cent decrease in cholesterol, a 34 per cent decrease in triglycerides and a 10 per cent decrease in LDL-C levels, as well as a 19 per cent decrease in cholesterol/high-density lipoprotein risk.52
Policosanol use has also achieved some interesting results. Like most avenues of research, that for policosanol began with animal studies showing lipid-lowering effects. In an early study, 5?200mg/kg policosanol orally administered for four weeks to normocholesterolaemic rabbits reduced total cholesterol and LDL-C in a dose-dependent manner. Triglyceride levels for treated and control animals were also different, but the reduction observed was not dose dependent.53
As studies moved to humans, positive effects on various lipid parameters have been observed in hypercholesterolaemic subjects.54 The issue regarding triglycerides is less clear, though the preponderance of evidence suggests that it may not affect this aspect of lipid metabolism.55 Still, many of the studies showing favourable56,57 or unfavourable effects54,55 were performed at low doses (eg, 10mg/day). Again, issues of dose dependency are always a concern since two studies using higher doses (20?40mg/day) suggest that triglyceride modulation is indeed possible with policosanol treatment.58
Creatine produced one of the most obscure findings when our group showed that the popular sport supplement had profound lipid-altering properties, including an approximate 25 per cent reduction in triglycerides after eight weeks of supplementation—an effect that persisted even after four weeks of treatment withdrawal.59 Although our study used hypercholesterolaemic participants, data in those with normal cholesterol are equivocal.60,61
Lp(a) lipoprotein is a low-density lipoprotein particle in which apolipoprotein B-100 is linked to a glycoprotein, apoprotein(a).62 Basic research indicates that Lp(a) lipoprotein plays a vital role in the development of arterial blockage by impairing fibrinolyis, thereby increasing plaque buildup.63 Although investigators have demonstrated its presence in atherosclerotic plaque, prospective studies of Lp(a) and the risk of vascular disease in middle-aged populations have yielded inconclusive results.64,65,66 However, emerging evidence suggests that the atherogenic effects of Lp(a) lipoprotein may be age- and sex-specific.67 To date, no data show that lowering Lp(a) leads to clinical benefit, yet a meta-analysis of 27 prospective studies showed that, although Lp(a) levels are only weakly correlated with classical vascular risk factors, they are associated with coronary heart disease risk.65
One interesting strategy for reducing Lp(a) levels is the elimination of trans fatty acids.68 However, a difficulty in examining supplements? effects is that many interventions may influence Lp(a) indirectly through other lipid markers.
Vitamin C research provides one of the more interesting theories regarding Lp(a). Nobel Prize laureate Linus Pauling proposed that Lp(a) may be a surrogate or substitute for ascorbate, or vitamin C.69 Based on his research, Pauling noted that Lp(a) is found in the blood of primates and the guinea pig, which have lost the ability to synthesise ascorbate. Thus, the hypothesis is that high Lp(a) is a function of low vitamin C levels.69
Niacin is believed to increase serum HDL-C levels by blocking the uptake of apolipoprotein A-I, a major component of HDL-C, at the liver.32 Niacin also increases the protective HDL component of cholesterol.70 Globally, niacin has been shown to decrease various lipid indices and Lp(a) by 34 per cent.71
Other nutrients have secondary effects on Lp(a). An example relates to the strong linkage Lp(a) has to those individuals with elevated homocysteine levels. Although homocysteine is reviewed above, similar types of vitamin intake alone or in combination may influence Lp(a). The singular vitamin candidates showing a relationship with Lp(a) are vitamins E,72 B6 and folate.31 Combined multivitamin therapy also appears to show efficacy.73
Furthermore, the relationship with homocysteine may be linked indirectly to the vitamin C hypothesis, because vitamin C protects LDL-C from homocysteine-mediated oxidation.74 Thus, reducing homocysteine may in turn reduce LDL-C oxidation. Other candidates for combination therapy also include garlic and omega-3 fatty acids.75,76
C-reactive protein (CRP) is an acute-phase reactant that immediately responds to tissue injury, illness, exercise, malignancy or any other inflammatory event. Studies have shown a positive association between CRP and coronary artery disease. In a survey of 388 British men aged 50 to 69, the prevalence of coronary artery disease increased 1.5-fold for each doubling of CRP concentration. Follow-up data from this same group confirmed this observation.77,78 Multiple prospective studies have also demonstrated that baseline CRP is a good marker of future cardiovascular events.79,80,81
One of the postulated reasons that CRP is indicative of CVD is its relationship to plaque in the arterial walls. The theory holds that diseased arteries typically contain inflammatory cells, and the rupture of plaque is a mechanism for acute myocardial infarction and acute coronary syndrome. The most common site of plaque rupture is the shoulder region where inflammatory cells are most prominent. Thus the release of acute-phase reactants such as CRP is a potential marker of ?unstable? plaque and underlying atherosclerosis.
On this note, some caution must be observed, even when CPR is elevated, since other triggering mechanisms also acutely increase CRP, particularly 24 to 72 hours post event. These include exercise, asthma, arthritis and other forms of inflammatory stimuli, as well as the ingestion of certain food types,82 including the possibility of the popular dietary supplement conjugated linoleic acid.83
Diet is a major environmental source of pro-inflammatory AGEs (heat-generated advanced glycation end products), whose effect in humans remains unclear. We explored the effects of two equivalent diets, one regular (high AGE, H-AGE) and the other with five-fold lower AGE (L-AGE) content on inflammatory mediators of 24 diabetic subjects: 11 in a two-week crossover and 13 in a six-week study. After two weeks on H-AGE, serum AGEs increased by 64.5 per cent and on L-AGE decreased by 30 per cent. Importantly, C-reactive protein increased by 35 per cent on H-AGE and decreased by 20 per cent on L-AGE, and vascular adhesion molecule-1 declined by 20 per cent on L-AGE and increased by 4 per cent on H-AGE. Serum AGEs were increased by 28.2 per cent on H-AGE and reduced by 40 per cent on L-AGE, whereas AGE low-density lipoprotein was increased by 32 per cent on H-AGE and reduced by 33 per cent on L-AGE diet.
Thus, in diabetes, dietary AGEs promote inflammatory mediators, leading to tissue injury. Restriction of dietary AGEs suppresses these effects.
Vitamins E, B6 and C appear to be primary nutrients that may affect CRP. Research has shown that a high intake of vitamin E, approximately 1,200IU/day, reduces CRP in normal volunteers and patients with Type 2 diabetes. 86 The specific form of vitamin E used in this trial was alpha-tocopherol. 86 Note that some Internet sites argue that other tocopherol forms are more biologically active and thus more potent. However, no data exists to show that other forms lower CRP.
In cross-sectional epidemiology studies, plasma concentrations of pyridoxal 5?-phosphate (PLP), the active form of vitamin B6, are associated with lower CRP concentrations.87 Data from our group have confirmed these observations clinically.88
In our study, participants consumed a 22-component multivitamin consisting of vitamins E (800IU), C (2,000mg) B6 and B12 as its primary ingredients, as well as lycopene. By analysing plasma concentrations of each of these vitamins, we found that individuals with CRP >1.0mg/L showed the greatest response to treatment and that higher plasma concentrations of B6 and C were associated with a greater reduction in CRP.88 Other groups have also made the vitamin C connection.89,90
As stated earlier in this article, high blood concentrations of any molecule do not necessarily mean that they are the primary effectors of the target that is being examined—in this case, CRP. They merely show the relationship between the two variables. Further complicating the issue is that one group of investigators has reported no effect for vitamins C or E following three years of supplementation.91 Unfortunately, this group administered vitamin E (136IU/day) and vitamin C (500mg/day) in doses well below what would be considered efficacious.
Foods such as tomato juice and possibly bing cherries may suppress CRP.92,93 To assess the physiologic effects of cherry consumption, we measured plasma urate, antioxidant and inflammatory markers in 10 healthy women who consumed bing sweet cherries. The women, aged 22?40 years, consumed two servings (280g) of cherries after an overnight fast. Blood and urine samples were taken before the cherry dose, and at one-and-a-half, three and five hours post-dose. Plasma urate decreased five hours post-dose. Urinary urate increased post-dose. Plasma C-reactive protein and nitric oxide concentrations had decreased marginally three hours post-dose, whereas plasma albumin and tumour necrosis factor-alpha were unchanged.
The vitamin C content of the cherries was solely as dehydroascorbic acid, but post-dose increases in plasma ascorbic acid indicated that dehydroascorbic acid in fruits is bioavailable as vitamin C. The decrease in plasma urate after cherry consumption supports the reputed anti-gout efficacy of cherries. The trend toward decreased inflammatory indices (CRP and nitric oxide) adds to the in-vitro evidence that compounds in cherries may inhibit inflammatory pathways.92
Two recent small-sample studies showed that CRP can be affected using a whole-foods approach inclusive of tomatoes and bing cherries.92,93 For tomato juice, investigators in this study compared daily supplementation of tomato juice (500ml/day), vitamin E (800IU/day) and vitamin C (500mg/day) or a placebo in 57 patients with well-controlled Type 2 diabetes. After four weeks and in correspondence to an increase in vitamin E and lycopene blood levels, those receiving the treatment arm reduced CRP by 49 per cent.
This observation speaks well for a mixed food/vitamin approach, given the high lycopene content of tomato juice.
An emerging area of research involves the potential use of cherries. Recently, investigators examined 10 healthy women who consumed bing sweet cherries on CRP.92 This study was a short-duration trial examining the acute effects of cherry intake (280g, about 2.4 cups) on CRP following an overnight fast. Although this early finding regarding cherries is interesting, it should also be noted that this effect was noted three hours after eating. Therefore, it remains to be seen whether longer studies will also show a reduction in fasting levels.
Overall, the studies of nutritional interventions affecting risk factors for CVD are, to say the least, multi-factorial. Complicating the issue is that nutrition and disease are replete with ?collinear? variables that are interrelated. Fortunately, many of the factors related to nutrition affect multiple secondary factors and can be integrated quite easily into a daily supplementation routine aimed at fortifying sub-optimal nutrition practices.
How these interventions will affect the overall disease process as measured by mortality outcomes remains to be seen. While the data accumulated to date are encouraging, longer trials are still needed in order to draw definitive answers.
Conrad Earnest, PhD, FACSM, is director of the Center for Human Performance & Nutrition Research at The Cooper Institute Centers for Integrated Health Research, Dallas, Texas.
Respond: [email protected] Correspondences will be forwarded to the author.
1. Brown BG, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92.
2. Rimm EB, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993;328:1450-6.
3. Enstrom JE, et al. Vitamin C intake and mortality among a sample of the United States population. Epidemiology 1992;3:194-202.
4. Stampfer MJ, et al. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993;328:1444-9.
5. Stephens NG, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-6.
6. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-tocopherol, Beta-carotene Cancer Prevention Study Group. N Engl J Med 1994;330:1029-35.
7. Weisburger JH. Nutritional approach to cancer prevention with emphasis on vitamins, antioxidants and carotenoids. Am J Clin Nutr 1991;53:S226-S37.
8. Malinow MR, et al. Homocyst(e)ine, diet and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999:99(1);178-82.
9. Selhub J, et al. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. J Am Med Assn 1993;270:2693-8.
10. Robinson K, et al. Low circulating folate and vitamin B6 concentrations: risk factors for stroke, peripheral vascular disease and coronary artery disease. European COMAC Group. Circulation 1998;97:437-43.
11. Bostom AG, et al. High dose-B-vitamin treatment of hyperhomocysteinemia in dialysis patients. Kidney Int 1996;49:147-52.
12. Guttormsen AB, et al. Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (> or = 40 micromol/liter). The Hordaland Homocysteine Study. J Clin Invest 1996;98:2174-83.
13. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists? Collaboration. Brit Med J 1998;316:894-8.
14. Franken DG, et al. Treatment of mild hyperhomocysteinemia in vascular disease patients. Arterioscler Thromb 1994;14:465-70.
15. Bostom AG, et al. Treatment of hyperhomocysteinemia in renal transplant recipients. A randomized, placebo-controlled trial. Ann Intern Med 1997;127:1089-92.
16. Earnest C, et al. Efficacy of a complex multivitamin supplement. Nutrition 2002;18:738-42.
17. Earnest CP, et al. Complex multivitamin supplementation improves homocysteine and resistance to LDL-C oxidation. J Am Coll Nutr 2003;22:400-7.
18. Ubbink JB, et al. Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine. Clin Chem 1995;41:1033-7.
19. Malinow MR, et al. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med 1998;338:1009-15.
20. Jacques PF, et al. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449-54.
21. Ubbink JB, et al. Hyperhomocysteinemia and the response to vitamin supplementation. Clin Investig 1993;71:993-8.
22. Daubner SC, et al. Purification and properties of methylenetetrahydrofolate reductase from pig liver. J Biol Chem 1982;257:140-5.
23. Shimakawa T, et al. Vitamin intake: a possible determinant of plasma homocyst(e)ine among middle-aged adults. Ann Epidemiol 1997;7:285-93.
24. Garg R, et al. Niacin treatment increases plasma homocyst(e)ine levels. Am Heart J 1999;138:1082-7.
25. Broekmans WM, et al. Fruits and vegetables increase plasma carotenoids and vitamins and decrease homocysteine in humans. J Nutr 2000;130:1578-83.
26. Nagata C, et al. Soy product intake is inversely associated with serum homocysteine level in premenopausal Japanese women. J Nutr 2003;133:797-800.
27. Jenkins DJ, et al. Effects of high- and low-isoflavone soyfoods on blood lipids, oxidized LDL, homocysteine and blood pressure in hyperlipidemic men and women. Am J Clin Nutr 2002;76:365-72.
28. Hermansen K, et al. Beneficial effects of a soy-based dietary supplement on lipid levels and cardiovascular risk markers in Type 2 diabetic subjects. Diabetes Care 2001;24:228-33.
29. Wilcken DE, et al. Homocystinuria: the effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med 1983;309:448-53.
30. Mudd SH, et al. Disorders in transsulfuration. In: Scriver CR, et al., editors. The Metabolic and Molecular Basis of Metabolic Disease. New York: McGraw Hill; 1995. p 1279-1327.
31. Frohlich JJ. Lipoproteins and homocyst(e)ine as risk factors for atherosclerosis: assessment and treatment. Can J Cardiol 1995;11 Suppl C:18C-23C.
32. Piepho RW. The pharmacokinetics and pharmacodynamics of agents proven to raise high-density lipoprotein cholesterol. Am J Cardiol 2000;86:35L-40L.
33. Franceschini G, et al. Pharmacological control of hypertriglyceridemia. Cardiovasc Drugs Ther 1993;7:297-302.
34. Capurso A. Drugs affecting triglycerides. Cardiology 1991;78:218-25.
35. Chojnowska-Jezierska J, et al. Prolonged treatment with slow release nicotinic acid in patients with type II hyperlipidemia. Pol Arch Med Wewn 1997;98:391-9.
36. Squires RW, et al. Low-dose, time-release nicotinic acid: effects in selected patients with low concentrations of high-density lipoprotein cholesterol. Mayo Clin Proc 1992;67:855-60.
37. Tsalamandris C, et al. Complementary effects of pravastatin and nicotinic acid in the treatment of combined hyperlipidaemia in diabetic and non-diabetic patients. J Cardiovasc Risk 1994;1:231-9.
38. Vanschoonbeek K, et al. Fish oil consumption and reduction of arterial disease. J Nutr 2003;133:657-60.
39. Chan DC, et al. Randomized controlled trial of the effect of n-3 fatty acid supplementation on the metabolism of apolipoprotein B-100 and chylomicron remnants in men with visceral obesity. Am J Clin Nutr 2003;77(2):300-7.
40. Laidlaw M, Holub BJ. Effects of supplementation with fish oil-derived n-3 fatty acids and gamma-linolenic acid on circulating plasma lipids and fatty acid profiles in women. Am J Clin Nutr 2003;77(1):37-42.
41. Khan S, et al. Dietary long-chain n-3 PUFAs increase LPL gene expression in adipose tissue of subjects with an atherogenic lipoprotein phenotype. J Lipid Res 2002;43(6):979-85.
42. Lewis NM, et al. Serum lipid response to n-3 fatty acid enriched eggs in persons with hypercholesterolemia. J Am Diet Assoc 2000;100:365-7.
43. Jiang Z, et al. Consumption of n-3 polyunsaturated fatty acid-enriched eggs and changes in plasma lipids of human subjects. Nutrition 1993;9:513-8.
44. Bordia A, et al. Effect of essential oil of onion and garlic on experimental atherosclerosis in rabbits. Atherosclerosis 1977;26:379-86.
45. Bakhsh R, et al. Influence of garlic on serum cholesterol, serum triglycerides, serum total lipids and serum glucose in human subjects. Nahrung 1984;28:159-63.
46. Auer W, et al. Hypertension and hyperlipidaemia: garlic helps in mild cases. Br J Clin Pract Suppl 1990;69:3-6.
47. Rotzsch W, et al. Postprandial lipemia under treatment with Allium sativum. Controlled double-blind study of subjects with reduced HDL2-cholesterol. Arzneimittelforschung 1992;42:1223-7.
48. Simons LA, et al. On the effect of garlic on plasma lipids and lipoproteins in mild hypercholesterolaemia. Atherosclerosis 1995;113:219-25.
49. Berthold HK, et al. Effect of a garlic oil preparation on serum lipoproteins and cholesterol metabolism: a randomized controlled trial. J Am Med Assn 1998;279:1900-2.
50. Silagy C, et al. Garlic as a lipid lowering agent?a meta-analysis. J Royal Coll Phys London 1994;28:39-45.
51. Neil HA, et al. Garlic powder in the treatment of moderate hyperlipidaemia: a controlled trial and meta-analysis. J Royal Coll Phys London 1996;30:329-34.
52. Morcos NC. Modulation of lipid profile by fish oil and garlic combination. J Natl Med Assoc 1997;89:673-8.
53. Arruzazabala ML, et al. Cholesterol-lowering effects of policosanol in rabbits. Biol Res 1994;27:205-8.
54. Pons P, et al. Effects of successive dose increases of policosanol on the lipid profile of patients with type II hypercholesterolaemia and tolerability to treatment. Intl J Clin Pharmacol Res 1994;14:27-33.
55. Canetti M, et al. A two-year study on the efficacy and tolerability of policosanol in patients with type II hyperlipoproteinaemia. Intl J Clin Pharmacol Res 1995;15:159-65.
56. Castano G, et al. Effects of policosanol on older patients with hypertension and type II hypercholesterolaemia. Drugs R D 2002;3:159-72.
57. Castano G, et al. Comparison of the efficacy and tolerability of policosanol with atorvastatin in elderly patients with type II hypercholesterolaemia. Drugs Aging 2003;20:153-63.
58. Castano G, et al. Effects of policosanol 20 versus 40mg/day in the treatment of patients with type II hypercholesterolemia: a six-month double-blind study. Int J Clin Pharmacol Res 2001;21:43-57.
59. Earnest CP, et al. High-performance capillary electrophoresis-pure creatine monohydrate reduces blood lipids in men and women. Clin Sci (London) 1996;91:113-8.
60. Arciero PJ, et al. Comparison of creatine ingestion and resistance training on energy expenditure and limb blood flow. Metabolism 2001;50:1429-34.
61. Volek JS, et al. No effect of heavy resistance training and creatine supplementation on blood lipids. Int J Sport Nutr Exerc Metab 2000;10:144-56.
62. Gaubatz JW, et al. Human plasma lipoprotein [a]. Structural properties. J Biol Chem 1983;258:4582-9.
63. Loscalzo J. Lipoprotein(a). A unique risk factor for atherothrombotic disease. Arteriosclerosis 1990;10:672-9.
64. Ariyo A, et al. Lipoprotein(a), lipids, aspirin and risk of myocardial infarction in the Physician?s Health Study. J Cardiovasc Risk 1998;5:273-8.
65. Danesh J, et al. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation 2000;102:1082-5.
66. Craig WY, et al. Lipoprotein(a) as a risk factor for ischemic heart disease: meta-analysis of prospective studies. Clin Chem 1998;44:2301-6.
67. Sunayama S, et al. Lack of increased coronary atherosclerotic risk due to elevated lipoprotein(a) in women > or = 55 years of age. Circulation 1996;94:1263-8.
68. Nelson GJ. Dietary fat, trans fatty acids and risk of coronary heart disease. Nutr Rev 1998;56:250-2.
69. Rath M, et al. Hypothesis: lipoprotein(a) is a surrogate for ascorbate. Proc Natl Acad Sci USA 1990;87:6204-7.
70. Sakai T, et al. Niacin, but not gemfibrozil, selectively increases LP-AI, a cardioprotective subfraction of HDL, in patients with low HDL cholesterol. Arterioscler Thromb Vasc Biol 2001;21:1783-9.
71. Carlson LA, et al. Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid. J Intern Med 1989;226:271-6.
72. Beaudeux JL, et al. Resistance of lipoprotein(a) to lipid peroxidation induced by oxygenated free radicals produced by gamma radiolysis: a comparison with low-density lipoprotein. Biochem J 1996;314(Pt 1) :277-84.
73. Heinimann K, et al. Lipoprotein(a) and plasma lipids in 429 elderly and very old subjects: significance as risk factor, effect of nutrition and life style. Schweiz Med Wochenschr 1996;126:1487.
74. Alul RH, et al. Vitamin C protects low-density lipoprotein from homocysteine-mediated oxidation. Free Radical Biol & Med 2003;34:881-91.
75. Byrne DJ, et al. A pilot study of garlic consumption shows no significant effect on markers of oxidation or sub-fraction composition of low-density lipoprotein including lipoprotein(a) after allowance for non-compliance and the placebo effect. Clin Chim Acta 1999;285:21-33.
76. Herrmann W, et al. Comparison of effects of N-3 to N-6 fatty acids on serum level of lipoprotein(a) in patients with coronary artery disease. Am J Cardiol 1995;76:459-62.
77. Mendall MA, et al. C-reactive protein: relation to total mortality, cardiovascular mortality and cardiovascular risk factors in men. Eur Heart J 2000;21:1584-90.
78. Mendall MA, et al. C reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study. Brit Med J 1996;312:1061-5.
79. Sesso HD, et al. C-reactive protein and the risk of developing hypertension. J Am Med Assn 2003;290:2945-51.
80. Blake GJ, et al. Blood pressure, C-reactive protein and risk of future cardiovascular events. Circulation 2003;108:2993-9.
81. Ridker PM, et al. C-reactive protein, inflammation and coronary risk. Cardiol Clin 2003;21:315-25.
82. Vlassara H, et al. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc Natl Acad Sci USA 2002;99(24):15596-601.
83. Riserus U, et al. Supplementation with conjugated linoleic acid causes isomer-dependent oxidative stress and elevated C-reactive protein: a potential link to fatty acid-induced insulin resistance. Circulation 2002;106:1925-9.
84. Ridker PM, et al. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) Investigators. Circulation 1999;100:230-5.
85. Albert MA, et al. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. J Am Med Assn 2001;286:64-70.
86. Devaraj S, et al. Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and Type 2 diabetic patients. Free Radical Biol & Med 2000;29:790-2.
87. Friso S, et al. Low circulating vitamin B6 is associated with elevation of the inflammation marker C-reactive protein independently of plasma homocysteine levels. Circulation 2001;103:2788-91.
88. Church TS, et al. Reduction of C-reactive protein levels through use of a multivitamin. Am J Med 2003;115:702-7.
89. Sanchez-Moreno C, et al. Decreased levels of plasma vitamin C and increased concentrations of inflammatory and oxidative stress markers after stroke. Stroke 2004;35:163-8.
90. Langlois M, et al. Serum vitamin C concentration is low in peripheral arterial disease and is associated with inflammation and severity of atherosclerosis. Circulation 2001;103:1863-8.
91. Bruunsgaard H, et al. Long-term combined supplementations with alpha-tocopherol and vitamin C have no detectable anti-inflammatory effects in healthy men. J Nutr 2003;133:1170-3.
92. Jacob RA, et al. Consumption of cherries lowers plasma urate in healthy women. J Nutr 2003;133:1826-9.
93. Upritchard JE, et al. Effect of supplementation with tomato juice, vitamin E and vitamin C on LDL oxidation and products of inflammatory activity in Type 2 diabetes. Diabetes Care 2000;23:733-8.