© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Arginine Intake and Risk of Coronary Heart Disease Mortality in Elderly Men
From the Department of Chronic Diseases Epidemiology (C.M.O., E.J.M.F.) and the Division of Public Health Research (D.K.), National Institute of Public Health and the Environment, Bilthoven, the Netherlands, and the Department of Human Nutrition and Epidemiology (C.M.O., M.J.v.E., F.J.K.), Wageningen University, Wageningen, the Netherlands.
Correspondence to Claudia M. Oomen, MSc, Department of Chronic Diseases Epidemiology, National Institute of Public Health and the Environment, Antonie van Leeuwenhoeklaan 9, PO Box 1, 3720 BA Bilthoven, Netherlands. E-mail claudia.oomen{at}rivm.nl
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Abstract |
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Abstract—From experimental studies, the hypothesis is derived that the amino acid arginine, the precursor of NO, could restore the impaired endothelial function and increased platelet activation observed in atherosclerosis. We investigated whether dietary intake of arginine is associated with reduced coronary heart disease risk in elderly persons. The study population consisted of 806 men aged 64 to 84 years at baseline who participated in the Zutphen Elderly Study, a population-based cohort followed up for 10 years. Information about habitual food consumption was collected by use of the cross-check dietary history method. Ninety (11.2%) of the 806 men died from coronary heart disease. Mean±SD baseline arginine intake was 4.35±1.07 g/d. Meat was the main source of arginine intake (37.1%), followed by bread (13.1%) and milk and milk products (12.1%). Arginine intake was not associated with coronary heart disease mortality. After adjustment for age, the relative risk (RR) for the medium tertile of arginine intake was 0.72 (95% CI 0.44 to 1.18), and the RR for the highest tertile was 0.71 (95% CI 0.43 to 1.19, P for trend=0.19) compared with the lowest tertile of arginine intake. After additional adjustment for history of coronary heart disease and diabetes mellitus, energy intake, body mass index, smoking habit, physical activity, and other relevant dietary and biological risk factors, the RR was 1.86 (95% CI 1.06 to 3.27) for the medium intake and 1.56 (95% CI 0.83 to 2.93) for the highest intake (P for trend=0.17). These results do not support the hypothesis that dietary arginine intake lowers the risk of coronary heart disease mortality.
Key Words: arginine • diet • coronary heart disease • elderly • epidemiology
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Introduction |
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The discovery of NO as a signaling molecule in the cardiovascular system was rewarded with the 1998 Nobel Prize in Medicine. The semiessential amino acid L-arginine is the precursor of NO. It has been demonstrated that administration of L-arginine can improve endothelium-dependent vascular relaxation through the release of NO.1 Chronic dietary supplementation of L-arginine in hypercholesterolemic animals has been associated with reduced atherosclerosis and antiatherogenic effects, such as reduction in surface area and intimal thickness of atheromatous lesions, decrease of platelet aggregation, and attenuation of cell proliferation and of vascular monocyte accumulation.2 3 4 5 6 7 8
In humans, endothelial dysfunction could be restored after dietary supplementation9 10 11 12 and intravenous administration of L-arginine13 14 15 in patients with hypercholesterolemia,9 13 14 heart failure,12 and nonobstructive or advanced coronary artery disease.10 11 15 Reduction in platelet aggregation by L-arginine has also been observed.16 17 18
Consequently, arginine was recently presented as a possible new pharmacological therapy for the atherogenic process leading to coronary heart disease.19 Antiatherogenic effects of arginine are especially demonstrated in human subjects with more or less advanced atherosclerosis. Coronary atherosclerosis is increasingly present in the elderly. Possibly, arginine is associated with reduced coronary heart disease risk in elderly persons. Therefore, we investigated the hypothesis that dietary arginine intake is inversely associated with coronary heart disease mortality among participants in the Zutphen Elderly Study.
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Methods |
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Study Population
The study population consisted of men who participated in the Zutphen Elderly Study, an extension of the Zutphen Study, the Dutch contribution to the Seven Countries Study.20 In 1960, the Zutphen Study started with a cohort of 878 men from Zutphen (the Netherlands) born between 1900 and 1919. In 1985, 367 of the 555 participants who were still alive were reexamined. In addition, 711 other men from the town of Zutphen in the same age category were asked to participate. A total of 939 men (response rate 74%) were examined in 1985, and complete information on diet and risk factors was available for 806 men. In 1990, 781 of these 939 men were still alive, and 560 took part in a follow-up examination. Dietary intake in 1990, together with complete information on diet and risk factors at baseline (1985) was available for 508 men.
Data Collection
Dietary and medical examinations were completed between March
and June 1985 and after 5 years of follow-up, between March and June
1990. Information about the habitual food consumption was collected by
use of the cross-check dietary history method, adapted to the Dutch
situation.21 Participants, together with the person who
prepared the meals, were interviewed about their usual food consumption
pattern during weekdays and weekends for the 2 to 4 weeks preceding the
interview. Quantities of food bought per week were used to calculate
and verify the food consumption of a participant on an average
weekday.
Nutrient intake data, including ethanol, were based on the Dutch food table.22 Because of lack of information on the amino acid composition of Dutch foods, arginine contents of chemical analysis were used, preferably from the United Kingdom23 and subsequently from the United States.24 The arginine contents were converted by use of the protein contents from the Dutch food table.22
During medical examinations, nonfasting venous blood samples were taken. Serum total cholesterol and HDL cholesterol were determined enzymatically.25 26 In 1995, serum total homocysteine was measured in serum stored at -20°C, as described previously.27 Weight and height were measured while participants were wearing underwear only, and body mass index was calculated (kilograms per meter squared). At the end of the physical examinations, blood pressure was measured twice with participants in the supine position. Information on smoking status (nonsmoker, exsmoker, or current smoker), medication use, and history of hypertension and diabetes mellitus was obtained by a standardized questionnaire. Patients with insulin-dependent and non–insulin-dependent diabetes mellitus were considered in the present study. Minutes of physical activity (mainly walking, cycling, hobbies, sports, gardening, and work) per week were calculated by use of a self-administered questionnaire originally designed for retired men.28 Information regarding a history of coronary heart disease was obtained by using the Dutch translation of the Rose questionnaire.29
Follow-Up
Information involving the vital status of all participants was
obtained from the municipal registries until January 1995. Three
participants were lost to follow-up. Information about the cause of
death was obtained from the Dutch Central Bureau of Statistics for
deaths occurring between baseline assessment and June 1990, after
verification with hospital discharge data and information from the
deceased’s general practitioners, and from the hospital
discharge data and/or participants’ general practitioners
for deaths occurring thereafter, and if such information was not
available, from the Dutch Central Bureau of Statistics. Causes of death
were coded according to the ninth revision of the International
Classification of Diseases (ICD). Coronary heart disease refers
to ICD codes 410 to 414. Because the underlying cause of death in the
elderly is often difficult to determine, the primary (n=84) and the
secondary (n=6) causes of death were both considered in the
analysis.
Statistical Methods
Differences in baseline characteristics of the participants
between tertiles of arginine intake were evaluated by ANOVA for
normally distributed variables, by Kruskal-Wallis test for skewed
variables, and by 
2 test for categorical
variables. Pearson correlation coefficients
(rp) were calculated between the intake of
arginine and other dietary factors.
Energy-adjusted nutrient intake (ie, arginine) was computed as residuals from the regression model, with energy intake as the independent variable and nutrient intake as the dependent variable.30 Before computing the residuals of nutrient intake, the logarithmic transformation of each nutrient variable, including arginine, was calculated to improve the normality. Cox proportional hazards (survival) analysis was used to calculate crude and adjusted relative risks (RRs), 95% CIs, and probability values for linear trend. The lowest tertile of arginine intake was taken as a reference group. Several multivariate analyses were performed to take into account potential confounding by major risk factors such as age, history of coronary heart disease, smoking status, body mass index, and other factors associated with arginine intake and potentially associated with coronary heart disease mortality. To evaluate confounding, a value of P<0.2 was considered. Energy-adjusted analysis included the energy-adjusted tertiles of arginine intake plus a term for energy intake. Interactions between arginine intake and relevant factors, such as age, history of coronary heart disease, and smoking status, were explored to determine whether the association between arginine intake and coronary heart disease mortality differed among subgroups of the population. Proportional hazards analyses, including arginine intake and all the covariables as time-dependent covariates, were also performed. The baseline measurement (1985) for the first 5 years of follow-up and the measurement for the second 5 years of follow-up (1990) were used. When the measurement for 1990 was not available, only the baseline measurement was used for the total follow-up period.
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Results |
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Baseline
Mean±SD baseline arginine intake of the 806 participants was 4.35±1.07 g/d. Meat provided the largest contribution to the total arginine intake (37.1%), followed by bread (13.1%) and milk and milk products (12.1%). A relatively large amount of arginine was also provided by peanuts (2.5%); this was due to the high percentage of arginine in the protein of peanuts (13.0%).
We examined the distribution of risk factors within categories of
arginine intake. Arginine intake was inversely associated with age,
history of coronary heart disease, and serum homocysteine
levels and positively associated with physical activity, alcohol use,
and history of diabetes mellitus (Table 1
). However, the distributions of other
risk factors did not differ appreciably across the arginine categories.
Concerning dietary factors, arginine intake was positively associated
with the intake of (saturated and unsaturated) fat, carbohydrates,
protein, fiber, cholesterol, and total energy (Table 2).
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Daily intake of arginine was strongly correlated with the intake of
energy (rp=0.65, P=0.001). After
adjustment for energy, the associations between arginine intake and
dietary factors were weakened (Table 3).
Energy-adjusted arginine intake remained significantly positively
associated with protein, dietary cholesterol, and fiber. In
addition, energy-adjusted arginine intake was positively associated
with history of diabetes mellitus and body mass index and inversely
associated with age and serum homocysteine levels (data not shown).
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Follow-Up
During 10 years of follow-up, 374 participants died, of which 90
(11.2%) died from coronary heart disease. In the crude
analysis, arginine intake was inversely associated with the
risk of coronary heart disease, with an RR of 0.63 (95% CI
0.38 to 1.04) for the highest intake (P for trend=0.07,
Table 4). In different
multivariate models, with potential confounding by
factors associated with arginine intake and potentially associated with
coronary heart disease mortality taken into account, no inverse
association between arginine intake and coronary heart disease
mortality was observed. Especially because of the adjustment for
energy intake, the RRs adjusted for age, history of coronary
heart disease, history of diabetes mellitus, and energy intake were
higher, 1.55 (95% CI 0.93 to 2.58) for the medium tertile and 1.19
(95% CI 0.68 to 2.07) for the highest tertile of arginine intake.
After adjustment for body mass index, cigarette smoking, physical
activity, alcohol consumption, and energy-adjusted intake of saturated
fatty acids, polyunsaturated fatty acids, cholesterol, and
fiber, the RRs for the medium and high tertiles compared with the
lowest were 1.68 (95% CI 0.97 to 2.90) and 1.48 (95% CI 0.80 to
2.72), respectively. Tests for linear trend were not statistically
significant. The inclusion of serum total and HDL
cholesterol, blood pressure, and serum homocysteine as
potential confounders in the analysis increased the RRs further
(Table 4).
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It may be questioned whether energy intake is a confounder in this population, because the association between energy intake and coronary heart disease mortality was not statistically significant in the adjusted analysis. Therefore, we repeated the multivariate analysis (the full model, with systolic blood pressure, cholesterol, and homocysteine) without adjustment for energy intake. The RR was 0.88 (95% CI 0.49 to 1.56) for the medium intake and 0.99 (95% CI 0.50 to 1.98) for the highest intake (P for trend=0.98).
We further examined whether the association between arginine intake and coronary heart disease mortality was modified by other risk factors, with use of an interaction term in the multivariate analysis. Only for age was a significant interaction observed. The association was significant and more strongly positive in men below the median age of 71 years and inverse (but not significant) in men aged >71 years.
Finally, to reduce the likelihood that our results were biased by changes in dietary intake and lifestyle, analyses were also performed with the use of time-dependent covariates. This resulted in significantly increased risks; in the full multivariate model, the RR was 2.19 (95% CI 1.22 to 3.95) for medium intake and 2.44 (95% CI 1.30 to 4.59) for the highest intake (P for trend=0.01).
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Discussion |
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This is the first observational study investigating the association between dietary arginine intake and coronary heart disease mortality. We observed no beneficial effect of dietary arginine intake on the risk of coronary heart disease in elderly men.
Our results regarding arginine intake and coronary heart disease mortality are not consistent with the antiatherogenic effects of arginine experimentally demonstrated in human subjects with more or less advanced atherosclerosis.9 10 11 12 13 14 15 16 17 18 In healthy subjects, some experimental studies observed no effect on endothelial function after infusion or supplementation of arginine.31 32 Plasma arginine levels in these subjects were also unaffected after supplementation.32 This finding suggests that at least under normal conditions, sufficient endogenous arginine can be synthesized to maintain the rate of NO synthesis.33 However, some findings in healthy young subjects showed that infusion of arginine could increase vasodilatation and blood viscosity and reduce platelet aggregation.34 Studies using a tracer for arginine also have shown that dietary arginine can affect the endogenous arginine metabolism and plasma arginine levels in humans.33 35 These findings and those from experiments in humans with a high risk profile for coronary heart disease suggest a relative lack of endogenous arginine for the synthesis of NO, which could be restored by arginine administration. Uncertainty remains regarding the exact conditions in which insufficient endogenous arginine is present.
An important limitation of the present study was that it included only men aged 64 to 84 years at baseline. The beneficial effects of arginine on vasodilatation might be higher in younger populations because stiff arteries are not as prevalent in the young. However, in the elderly, atherosclerosis is increasingly present, just as in the subjects of experiments in which the antiatherogenic effects of oral L-arginine supplementation were demonstrated. Subgroup analysis indicated that in the oldest men, arginine was inversely associated with coronary heart disease mortality, albeit nonsignificantly. On the basis of these data, however, generalizability with respect to other age groups and women is uncertain.
In experiments in which the antiatherogenic effects of oral L-arginine supplementation were demonstrated, subjects were supplemented with 3 to 21 g L-arginine per day during a short10 17 or long9 11 12 period. The dose used in those experiments was generally much higher than the average arginine intake in the present study. Therefore, it cannot be excluded that the effects of arginine on atherosclerosis are especially present when large amounts of arginine are supplemented and that the range of dietary arginine intake in our cohort was not wide enough to observe an association.
A true inverse association between arginine intake and coronary heart disease mortality could also be missed if the measurement of the arginine content of the diet is imprecise. Habitual food composition was measured by use of the cross-check dietary history method, which is acknowledged as a valid method in an epidemiological setting.21 Random misclassification of dietary exposure due to error in the quantification of arginine in food tables cannot be excluded. Plasma arginine levels were not measured; however, these might reflect short-term rather than long-term dietary intake because of endogenous synthesis and conversion of arginine.35 The estimate of daily average arginine intake of 4.4 g of the Zutphen elderly population was comparable to the estimated arginine intake of 4.2 g/d after 5 years of follow-up (rp=0.50, P=0.001) and to the estimated average arginine intake of the American diet of 5.4 g/d, which is based on the arginine contents of foods available in 1970.36 In addition, by use of the baseline measurement of arginine and the measurement after 5 years of follow-up, arginine intake was even more strongly positively associated with coronary heart disease mortality compared with the measurement using arginine intake at baseline only. Thus, it is unlikely that misclassification of dietary exposure explains our findings.
Because higher arginine intake was associated with a healthier lifestyle and diet, including a high energy intake, in our study population, we used several multivariate models to reduce residual confounding. A higher risk of coronary heart disease mortality with arginine intake was observed with the multivariate model. This apparent positive association is probably due to chance, because there is no biological explanation for this finding. Furthermore, the effect of L-arginine on coronary heart disease mortality could be confounded by other dietary factors that were not included in our analysis. Because arginine is derived from different foods, other dietary factors occurring in the same foods could have affected the results for arginine. For instance, in addition to arginine, nuts also contain other potentially protective constituents.37 Furthermore, arginine intake is highly associated with the intake of other amino acids, such as methionine (rp=0.89, P=0.001). However, our results are adjusted for serum homocysteine, the intermediate in the potential association between methionine and coronary heart disease. Also, other dietary factors influencing the arginine-NO pathway, such as L-glutamine38 39 or vitamin C,40 could have interfered with the role of arginine. Vitamin C could inhibit the inactivation of NO by oxygen-derived free radicals. However, adjustment for intake of vegetables, fruit, or vitamin C in the analysis did not appreciably change the results (data not shown).
In conclusion, we observed no association between dietary arginine intake and coronary heart disease mortality in a cohort of elderly men. However, this result cannot be generalized because of the elderly population studied and unmeasured dietary factors (potentially) associated with arginine. Additional observational studies are needed, preferably in other age groups in populations with a relatively high arginine intake or on more specific parameters, such as endothelial function. Furthermore, other lines of research, including studies involving biomarkers for arginine intake, should be carried out to confirm or reject the beneficial impact of arginine on coronary heart disease suggested by human and animal experiments.
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Acknowledgments |
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C.M. Oomen was partly supported by a grant from Unilever Research Laboratory, Vlaardingen, the Netherlands, to the Wageningen University.
Received November 11, 1999; accepted February 14, 2000.
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References |
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|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988;333:664–666.[Medline] [Order article via Infotrieve]
- Cooke JP, Singer AH, Tsao P, Zera P, Rowan RA, Billingham ME. Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest. 1992;90:1168–1172.
-
Tsao PS, Theilmeier G, Singer AH, Leung LL-K, Cooke
JP. L-Arginine attenuates platelet reactivity in
hypercholesterolemic rabbits. Arterioscler
Thromb. 1994;14:1529–1533.
[Abstract/Free Full Text] -
Tsao PS, McEvoy LM, Drexler H, Butcher EC, Cooke JP.
Enhanced endothelial adhesiveness in
hypercholesterolemia is attenuated by
L-arginine. Circulation. 1994;89:2176–2182.
[Abstract/Free Full Text] -
Aji W, Ravalli S, Szabolcs M, Jiang X, Sciacca RR,
Michler RE, Cannon PJ. L-Arginine prevents xanthoma development and
inhibits atherosclerosis in LDL receptor knockout mice.
Circulation. 1997;95:430–437.
[Abstract/Free Full Text] -
Okazaki J, Komori K, Kawasaki K, Eguchi D, Ishida M,
Sugimachi K. L-Arginine inhibits smooth muscle cell proliferation of
vein graft intimal thickness in hypercholesterolemic
rabbits. Cardiovasc Res. 1997;36:429–436.
[Abstract/Free Full Text] - Bode-Böger SM, Böger RH, Kienke S, Böhme M, Phivthong-ngam L, Tsikas D, Frölich JC. Chronic dietary supplementation with L-arginine inhibits platelet aggregation and thromboxane A2 synthesis in hypercholesterolaemic rabbits in vivo. Cardiovasc Res. 1998;37:756–764.[Medline] [Order article via Infotrieve]
- Böger RH, Bode-Böger SM, Kienke S, Stan AC, Nafe R, Frölich JC. Dietary L-arginine decreases myointimal cell proliferation and vascular monocyte accumulation in cholesterol-fed rabbits. Atherosclerosis. 1998;136:67–77.[Medline] [Order article via Infotrieve]
- Clarkson P, Adams MR, Powe AJ, Donald AE, McCredie R, Robinson J, McCarthy SN, Keech A, Celermajer DS, Deanfield JE. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest. 1996;97:1989–1994.[Medline] [Order article via Infotrieve]
- Adams MR, McCredie R, Jessup W, Robinson J, Sullivan D, Celermajer DS. Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease. Atherosclerosis. 1997;129:261–269.[Medline] [Order article via Infotrieve]
-
Lerman A, Burnett JC, Higano ST, McKinley LJ, Holmes
DR. Long-term L-arginine supplementation improves small-vessel
coronary endothelial function in humans.
Circulation. 1998;97:2123–2128.
[Abstract/Free Full Text] -
Rector TS, Bank AJ, Mullen KA, Tschumperlin LK, Sih R,
Pillai K, Kubo SH. Randomized, double-blind, placebo-controlled study
of supplemental oral L-arginine in patients with heart failure.
Circulation. 1996;93:2135–2141.
[Abstract/Free Full Text] - Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet. 1991;338:1546–1550.[Medline] [Order article via Infotrieve]
- Creager MA, Gallagher SJ, Girerd XJ, Coleman SM, Dzau VJ, Cooke JP. L-Arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest. 1992;90:1248–1253.
-
Bode-Böger SM, Böger RH, Alfke H, Heinzel
D, Tsikas D, Creutzig A, Alexander K, Frölich JC. L-Arginine
induces nitric oxide–dependent vasodilation in patients with critical
limb ischemia: a randomized, controlled study.
Circulation. 1996;93:85–90.
[Abstract/Free Full Text] -
Radomski MW, Palmer RMJ, Moncada S. An
L-arginine/nitric oxide pathway present in human platelets
regulates aggregation. Proc Natl Acad Sci U S A. 1990;87:5193–5197.
[Abstract/Free Full Text] - Wolf A, Zalpour C, Theilmeier G, Wang B, Ma A, Anderson B, Tsao PS, Cooke JP. Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J Am Coll Cardiol. 1997;29:479–485.[Abstract]
-
Diodati JG, Dakak N, Gilligan DM, Quyyumi AA. Effect of
atherosclerosis on
endothelium-dependent inhibition of platelet
activation in humans. Circulation. 1998;98:17–24.
[Abstract/Free Full Text] -
Cooke JP, Tsao PS. Arginine: a new therapy for
atherosclerosis? Circulation. 1997;95:311–312.
[Free Full Text] - Keys A, Aravanis C, Blackburn H. Epidemiological studies related to coronary heart disease: characteristics of men aged 40–59 in seven countries. Acta Med Scand. 1966;460(suppl):1–392.
-
Bloemberg BPM, Kromhout D, Obermann-de Boer GL, van
Kampen-Donker M. The reproducibility of dietary intake data assessed
with the cross-check dietary history method. Am J
Epidemiol. 1989;130:1047–1056.
[Abstract/Free Full Text] - Kommissie UCV. UCV tabel: uitgebreide voedingsmiddelentabel 1985. The Hague, the Netherlands: Voorlichtingsbureau voor de voeding (Nutrition Education Bureau); 1985.
- Paul AA, Southgate DAT. McCance and Widdowson’s The Composition of Foods. Amsterdam, the Netherlands/New York, NY/London, UK: Elsevier; 1978.
- US Department of Agriculture. USDA Nutrient Database for Standard Reference, release No. 11–1. Available at: http://www.nal.usda.gov/fnic/foodcomp. Accessed 1996.
- Siedel J, Schlumberger H, Klose S, Ziegenhorn J, Wahlefeld AW. Improved reagent for the enzymatic determination of serum cholesterol. J Clin Chem Clin Biochem. 1981;19:838–839.
-
Warnick GR, Benderson J, Albers JJ. Dextran
sulfate-Mg2+ precipitation procedure for
quantification of high density-lipoprotein cholesterol.
Clin Chem. 1982;28:1379–1388.
[Free Full Text] -
Stehouwer CDA, Weijenberg MP, van den Berg M, Jakobs C,
Feskens EJM, Kromhout D. Serum homocysteine and risk of
coronary heart disease and cerebrovascular disease in elderly
men: a 10-year follow-up. Arterioscler Thromb Vasc Biol. 1998;18:1895–1901.
[Abstract/Free Full Text] -
Caspersen CJ, Bloemberg BPM, Saris WHM, Merritt RK,
Kromhout D. The prevalence of selected physical activities and their
relation with coronary heart disease risk factors in elderly
men: the Zutphen Study, 1985. Am J Epidemiol. 1991;133:1078–1092.
[Abstract/Free Full Text] - Rose GA, Blackburn H. Cardiovascular Survey Methods. Geneva, Switzerland: World Health Organization; 1968.
-
Willett WC, Howe GR, Kushi LH. Adjustment for total
energy intake in epidemiologic studies. Am J Clin Nutr. 1997;65:1220S–1228S.
[Abstract/Free Full Text] - Baudoin SV, Bath P, Martin JF, Du Bois R, Evans TW. L-Arginine infusion has no effect on systemic haemodynamics in normal volunteers, or systemic and pulmonary haemodynamics in patients with elevated pulmonary vascular resistance. Br J Clin Pharmacol. 1993;36:45–49.[Medline] [Order article via Infotrieve]
- Chin-Dusting JPF, Alexander CT, Arnold PJ, Hodgson WC, Lux AS, Jennings GLR. Effects of in vivo and in vitro L-arginine supplementation on healthy human vessels. J Cardiovasc Pharmacol. 1996;28:158–166.[Medline] [Order article via Infotrieve]
-
Castillo L, Sanchez M, Vogt J, Chapman TE,
DeRojas-Walker TC, Tannenbaum SR, Ajami AM, Young VR. Plasma arginine,
citrulline, and ornithine kinetics in adults, with observations on
nitric synthesis. Am J Physiol. 1995;268:E360–E367.
[Abstract/Free Full Text] - Giugliano D, Marfella R, Verrazzo G, Acampora R, Coppola L, Cozzolino D, D’Onofrio F. The vascular effects of L-arginine in humans: the role of endogenous insulin. J Clin Invest. 1997;99:433–438.[Medline] [Order article via Infotrieve]
-
Castillo L, DeRojas TC, Chapman TE, Vogt J, Burke JF,
Tannenbaum SR, Young VR. Splanchnic metabolism of dietary
arginine in relation to nitric oxide synthesis in normal adult man.
Proc Natl Acad Sci U S A. 1993;90:193–197.
[Abstract/Free Full Text] - Visek WJ. Arginine needs, physiological state and usual diets: a reevaluation. J Nutr. 1986;116:36–46.
-
Hu FB, Stampfer MJ, Manson JE, Rimm EB, Colditz GA,
Rosner BA, Speizer FE, Hennekens CH, Willett WC. Frequent nut
consumption and risk of coronary heart disease in women:
prospective cohort study. BMJ. 1998;317:1341–1345.
[Abstract/Free Full Text] -
Wu G, Meininger CJ. Regulation of L-arginine synthesis
from L-citrulline by L-glutamine in endothelial cells.
Am J Physiol. 1993;265:H1965–H1971.
[Abstract/Free Full Text] - Arnal J, Münzel T, Venema RC, James NL, Bai C, Mitch WE, Harrison DG. Interactions between L-arginine and L-glutamine change endothelial NO production. J Clin Invest. 1995;95:2565–2572.
-
Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A.
Vitamin C improves endothelium-dependent vasodilation
by restoring nitric oxide activity in essential hypertension.
Circulation. 1998;97:2222–2229.
[Abstract/Free Full Text]
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J. Chen, P. Kuhlencordt, F. Urano, H. Ichinose, J. Astern, and P. L. Huang L-Arginine on Atherosclerosis in ApoE Knockout and ApoE/Inducible NO Synthase Double-Knockout Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2003; 23(1): 97 - 103. [Abstract] [Full Text] [PDF]
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 B. Venho, S. Voutilainen, V.-P. Valkonen, J. Virtanen, T. A Lakka, T. H Rissanen, M.-L. Ovaskainen, M. Laitinen, and J. T Salonen Arginine intake, blood pressure, and the incidence of acute coronary events in men: the Kuopio Ischaemic Heart Disease Risk Factor Study Am. J. Clinical Nutrition, August 1, 2002; 76(2): 359 - 364. [Abstract] [Full Text] [PDF]
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 E.J.M. Feskens, C M. Oomen, E. Hogendoorn, A. Menotti, and D. Kromhout Arginine intake and 25-year CHD mortality: the Seven Countries Study Eur. Heart J., April 1, 2001; 22(7): 611 - 612. [PDF]
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A. A Brown and F. B Hu Dietary modulation of endothelial function: implications for cardiovascular disease Am. J. Clinical Nutrition, April 1, 2001; 73(4): 673 - 686. [Abstract] [Full Text] [PDF]
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