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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Stroke. Author manuscript; available in PMC 2010 August 1.
Published in final edited form as:
PMCID: PMC2749947

Association of the Endogenous Nitric Oxide Synthase Inhibitor ADMA with Carotid Artery Intimal Media Thickness in the Framingham Heart Study Offspring Cohort


Background and Purpose

Higher plasma concentrations of the endogenous nitric oxides synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) are associated with increased risk of cardio- and cerebrovascular events and death, presumably by promoting endothelial dysfunction and subclinical atherosclerosis. We hypothesized that plasma ADMA concentrations are positively related to common carotid artery intimal media thickness (CCA-IMT) and to internal carotid (ICA)/bulb-IMT.


We investigated the cross-sectional relations of plasma ADMA with CCA-IMT and ICA/bulb-IMT in 2958 Framingham Heart Study participants (mean age 58 years, 55% women).


In unadjusted analyses, ADMA was positively related to both CCA-IMT (β per SD increment 0.012, p<0.001) and ICA/bulb IMT (β per SD increment 0.059, p<0.001). In multivariable analyses (adjusting for age, sex, systolic blood pressure, antihypertensive treatment, smoking status, diabetes, body mass index (BMI), Total to HDL cholesterol ratio, log C-reactive protein, and serum creatinine), plasma ADMA was not associated with CCA-IMT (p=0.991), but remained significantly and positively related to ICA/bulb IMT (β per SD increment 0.0246, p=0.002).


In our large community-based sample, we observed that higher plasma ADMA concentrations were associated with greater ICA/bulb-IMT but not with CCA-IMT. These data are consistent with the notion that ADMA promotes subclinical atherosclerosis in a site-specific manner, with a greater proatherogenic influence at known vulnerable sites in the arterial tree.

Index Words: Carotid Intimal Medial Thickness, Endothelium, Epidemiology, Risk Factors, Nitric Oxide


Carotid artery intimal media thickness (IMT) is a widely accepted indicator of subclinical atherosclerosis burden, with higher values being associated with an adverse cardiovascular prognosis. Consequently, carotid IMT has also been proposed as a surrogate endpoint for therapeutic interventions directed at lowering atherosclerotic burden.1, 2

Accumulating scientific evidence links asymmetric dimethylarginine (ADMA, an endogenous inhibitor of all major isoforms of nitric oxide synthase [NOS]), to cardio- and cerebrovascular disease.3, 4 Higher plasma ADMA concentrations are associated with increased risk of myocardial infarction, stroke, and total mortality in a broad spectrum of people in the general population5-7 and in patients with prevalent coronary heart disease,8, 9 septic shock10 and renal failure.11 It is widely assumed that the association of ADMA and adverse clinical events in these diverse samples is largely related to the attenuation of the vasculoprotective effects of NO, leading to endothelial dysfunction and subsequent atherosclerosis.4,12-15

Few clinical studies have directly related endogenous ADMA concentrations to the extent of atherosclerosis in community-based samples; thus ADMA has been related to CT coronary artery calcification in young adults.16 In 1999 Miyazaki et al. reported a strong positive correlation of ADMA with common carotid artery (CCA) intimal media thickness (IMT) in 122 clinically healthy Japanese,17 a finding that has been replicated in another Japanese sample18 and in smaller studies investigating patients with prevalent disease.19-21 Another recent report noted an inverse association of ADMA concentrations with IMT, thereby rendering the issue unclear.22 These prior studies were limited by modest sample sizes and referral biases. More recently ADMA was related to baseline CCA-IMT and to progression in CCA-IMT over 6 years in two community-based cohorts23, 24 of native American and Japanese persons. However, no study has assessed the association of ADMA with IMT of the carotid bulb and the proximal part of the internal carotid artery (ICA), a surprising omission given abundant clinical and experimental data suggesting that this vascular region may be especially vulnerable to attenuation of NO synthesis.25

We hypothesized that higher ADMA concentrations are associated with greater IMT in the CCA as well as in the ICA/bulb, and tested this hypothesis in the large, community-based Framingham Offspring Study cohort.


Participants and Covariates

We have detailed the selection criteria and design of the Framingham Heart Study elsewhere.26 The Framingham Offspring Study began in 1971 with the enrolment of 5124 participants, who were either the children of the original cohort participants or spouses of these children. The study protocol was approved by the Boston Medical Center Institutional Review Board, and all participants provided written informed consent.

Offspring cohort participants undergo routine examinations at the Heart Study clinic approximately once every four years. At each Heart Study visit, attendees undergo anthropometric measurements, medical history and physical examination, and laboratory assessment of cardiovascular risk factors. Of 3532 attendees at the sixth examination cycle (1995-1998), 3453 (98%) participants had plasma ADMA concentration measured. We excluded 413 individuals from the present investigation because of prevalent CVD including stroke, 124 were excluded for missing carotid information, 29 were excluded for missing ADMA, and 8 were excluded for creatinine greater than 2 mg/dL. After these exclusions, 2958 individuals (1622 women) remained eligible for the present investigation. Participants with prevalent cardiovascular disease (CVD) were excluded to avoid confounding by prevalent disease status. Also, if ADMA is associated with prevalent CVD and prevalent CVD is associated with greater IMT, we could find a positive association between ADMA and IMT that is simply an epiphenomenon.

Carotid Ultrasonography

At the sixth examination cycle, carotid ultrasonography was performed and images were analyzed according to a standardized protocol by a single trained sonographer using a single ultrasound machine (Toshiba Medical Systems, Tustin, California).27, 28 A high-resolution 7.5-MHz transducer was used for imaging the CCA, whereas a 5.0-MHz transducer was used for the carotid bulb and the ICA. The trained sonographer was blinded to the clinical information of the participants, and made IMT measurements, which were overread by 1 of the investigators (JP). Carotid IMT measurements were obtained from 2 diastolic images at 3 sites in each (right and left) carotid artery. These sites were at the level of the distal CCA, at the carotid artery bulb, and at the proximal ICA (defined as the first 2 cms). At each site the maximal IMT was assessed in the right near and far walls, and in the left near and far walls, thus giving 4 wall-segment measurements at each site. These 12 measurements were grouped into two sets. The mean of the 4 measurements recorded in the distal CCA was estimated as the mean maximal CCA-IMT. Thus the mean maximum wall thickness of the CCA was estimated as the mean of the maximum wall thicknesses for near and far wall on both the left and right sides: (mLNW+mLFW+mRNW+mRFW)/4. The mean of the 8 measurements recorded at the carotid bulb and proximal ICA sites was estimated as the mean maximal carotid bulb/ICA-IMT. We have previously reported good reproducibility for our measurement protocols, with intraclass correlation coefficients for mean maximal CCA-IMT and mean maximal ICA/bulb-IMT of 0.86 and 0.74, respectively.27

Determination of ADMA

ADMA was measured as detailed elsewhere) using a fully validated commercially available high-throughput liquid chromatography-tandem mass spectrometry assay (DLD Diagnostika, Hamburg, Germany).29, 30 The intra-assay and the inter-assay coefficients of variation (CV) were 3.2% and <5%, respectively.

Statistical Analyses

Means and standard deviations are presented to summarize continuous clinical, imaging and biochemical characteristics, and percentages are presented for categorical characteristics. We evaluated the distributional properties of the variables graphically, and log-transformed variables that were skewed. Pearson's correlation coefficient was calculated to assess correlations among the variables. T-tests were used for the baseline comparisons of continuous data.

It has previously been shown that the CCA and the ICA segments may differ with regard to their associations with risk common vascular risk factors.1,25 We, therefore, defined two vascular targets to be assessed, i.e, CCA-IMT and the ICA/bulb-IMT. The corresponding null hypothesis to be tested was that in a multivariable-adjusted model neither CCA-IMT nor the ICA/bulb-IMT is related to continuous ADMA concentrations. To account for the inflation of the alpha error due to analysis of two carotid IMT measurements, we applied a Bonferroni correction and defined a p <0.025 (0.05 divided by 2) as indicating statistical significance, and as the threshold required to reject the null hypothesis. All additional analyses were deemed exploratory, and a p value of <0.05 was considered statistically significant for these analyses.

We used multiple linear regression models to relate plasma ADMA concentrations (independent variable) to CCA-IMT and ICA/bulb-IMT (dependent variables), both sets of measurements being modelled as continuous untransformed variables, given their normal distributions. We did not observe effect modification by sex upon formal statistical testing for an interaction between ADMA and sex for CCA-IMT or ICA/bulb IMT measurements. Accordingly, all analyses were performed for pooled sexes.

We constructed two sets of multivariable models: a. Model 1 adjusted for age, sex and body mass index (BMI); b. Model 2 adjusted for age, sex, systolic blood pressure, antihypertensive treatment, smoking status, diabetes, body mass index (BMI), total to HDL cholesterol ratio, C-reactive protein (log-transformed), and serum creatinine (fully-adjusted model). We used a general linear model for analysis of covariance to estimate adjusted least squares means of the IMT measures across quartiles of plasma ADMA. We further evaluated the effect modification of ADMA by age (dichotomized at the median for the sample), diabetes (yes/no), smoking, and body mass index (≥30 kg/m2; yes/no) by incorporating corresponding interaction terms into the multivariable model 2; none of these interactions were statistically significant. We also evaluated effect modification by a composite measure of vascular risk, the Framingham risk score.31

All analyses were performed with SAS statistical software version 9.1 (SAS Institute 2002).


The baseline clinical and biochemical characteristics as well as distributions of carotid IMT measures of the 2958 participants (55% women) in the present investigation are displayed in Table 1.

Table 1
Characteristics of study sample.

Association of ADMA concentrations with CCA and ICA/bulb Intimal media thickness

In unadjusted analyses, ADMA was positively related to both CCA-IMT (β per SD increment 0.012, p<0.001) and ICA/bulb IMT (β per SD increment 0.059, p<0.001). Upon adjustment for other risk factors, ADMA remained positively related to ICA/bulb-IMT (p=0.002), but not to CCA-IMT (p=0.99). Table 2 displays the results of the multivariable-adjusted regression analyses relating ADMA concentrations (modeled as a continuous variable and as quartiles) to CCA-IMT and ICA/bulb-IMT. Correspondingly, we observed an increase of the ICA/bulb-IMT from the first to the fourth quartile of ADMA (p for trend=0.029), while there was no significant trend for CCA-IMT (p=0.39), as shown in Tables 2 and and33.

Table 2
Multivariable-adjusted* regression of common carotid artery intimal media thickness (CCA-IMT) and bulb/proximal internal carotid artery intimal media thickness (ICA/bulb-IMT) on plasma ADMA levels.
Table 3
Unadjusted and Adjusted Mean Intimal Medial Thickness (IMT) values by quartile categories of ADMA

Using GLM procedures we also assessed whether the ADMA concentration retains an independent association with ICA/bulb-IMT when accounting for the individual cardiovascular risk based on the Framingham Risk Score. The interaction between ADMA quartiles and Framingham Risk Score groups was not found significant (p=0.32), therefore the association of ADMA with ICA/bulb-IMT does not depend on the Framingham Risk Score. Subsequently, in a multivariable model controlling for Framingham Risk Score group, ADMA was associated with ICA/bulb-IMT, (p<0.001).


In our cross-sectional study of a large community-based sample, we observed a positive association of plasma ADMA concentrations with ICA/bulb-IMT but not with CCA-IMT.

Mechanisms underlying the association of plasma ADMA and ICA/bulb-IMT

The L-arginine-NO pathway is crucial for the regulation of vascular tone and protection of vascular integrity by preventing endothelial activation.32, 33 Premature atherosclerosis and spontaneous myocardial infarction were observed in a new mouse model deficient in all three NOS isoforms, which elegantly verifies the concept that failure of NO synthesis can promote generalized atherosclerosis.34 In a concentration range matching that observed in vivo inside cells, ADMA has discernable inhibitory effects on NO synthesis.35 Mice with partial ablation of the ADMA degrading enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) also have only moderately (30-50%) elevated plasma ADMA concentrations, but demonstrate endothelial dysfunction, increased vascular resistance, elevated blood pressure, and reduced cardiac output.36 In contrast, mice over-expressing DDAH1 or DDAH2 appear to be protected from vascular damage.37, 38 This is further supplemented by several clinical studies.3, 5, 8-12 Thus, our cross-sectional observations are consistent with the known association of ADMA with subclinical atherosclerosis in some prior reports.

An alternative explanation for the association of ADMA and ICA IMT would be that in patients with subclinical atherosclerosis higher ADMA concentrations are simply a marker of associated processes such as oxidative stress or concomitant renal dysfunction that impairs its generation, metabolism or excretion.39 We controlled for renal function by excluding individuals with overt renal dysfunction at baseline and adjusting for serum creatinine in all multivariable analyses.

Site-Specific Associations of ADMA

Several investigations have documented the differential responses of different anatomical vascular sites to systemic risk factors.40, 41 The varying association of ADMA with atherosclerotic lesions in carotid artery locations that are only centimetres apart is intriguing. This finding should however be interpreted with caution, since some prior studies did relate ADMA to CCA-IMT;18, 24 the absence of an associaation between ADMA and CCA-IMT in the present study may therefore be due to chance or may reflect differences in the stage of the disease at both sites as well as ethnicity and other differences between our sample and the prior cohort studies. Yet, for the carotid artery, it has frequently been reported that the region of the bulb and the adjacent part of the ICA appear to be more sensitive to circulating risk factors for atherosclerosis than the common carotid artery.42, 43, 44, 45, 46 A major physiological distinction between the CCA and the ICA/bulb are differences in flow patterns (see25 for an excellent review). For anatomical reasons, laminar flow in the carotid bulb is frequently disturbed, leading to insufficient stimulation of NOS expression and activation. Thus, it is conceivable that this location may be especially sensitive to further impairment of NO synthesis by higher ADMA concentrations. The differential association of ADMA with CCA- and ICA-IMT might also reflect a higher prevalence of atherosclerosis and plaque formation in the ICA-IMT and could suggest that ADMA is associated with more severe lesions.

Study Strength and Limitations

The strengths of our investigation include the large, community-based and well-characterized sample, and the determination of ADMA blinded to IMT measurements. Key limitations of our study include its cross-sectional design that precludes any causal inferences, and the predominantly white sample, which limits the generalizability of our observations to other ethnicities.


In our large community-based sample, we observed that higher plasma concentrations of the endogenous NOS inhibitor ADMA were associated with greater ICA/bulb-IMT but not with greater CCA-IMT. These findings are consistent with the promotion of subclinical atherosclerosis in a site-specific manner (i.e., at sites of arterial vulnerability) by circulating ADMA. Further, ADMA may serve as a biomarker for carotid disease and additional exploration of this pathway could further our understanding of the pathophysiology underlying the development of carotid atherosclerosis.


Grant Support: This work was supported by National Institutes of Health/National Heart, Lung, and Blood Institute Contract N01-HC-25195, N01HV28178, and 2K24HL04334 (Dr Vasan), the National Institute on Aging ( R01 AG16495; AG08122, Dr. Wolf), the National Institute of Neurological Disorders and Stroke ( R01 NS17950, Dr. Wolf) and the Deutsche Forschungsgemeinschaft grant Bo1431/4-1 Dr. Böger). The content is solely the responsibility of the authors and does not necessarily represent the official views of NINDS, NHLBI, NIA or NIH.


Conflict of Interest: Drs. Böger, Schwedhelm, and Maas are named as inventors on patents relating to analytical assays for methylarginines and receive modest royalties from these.

Financial Disclosures: No other authors reported financial disclosures.

Reference List

1. O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK., Jr Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999 January 7;340(1):14–22. [PubMed]
2. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007 January 30;115(4):459–67. [PubMed]
3. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992 March 7;339(8793):572–5. [PubMed]
4. Cooke JP. Asymmetrical dimethylarginine: the Uber marker? Circulation. 2004 April 20;109(15):1813–8. [PubMed]
5. Maas R, Schulze F, Baumert J, Lowel H, Hamraz K, Schwedhelm E, Koenig W, Boger RH. Asymmetric dimethylarginine, smoking, and risk of coronary heart disease in apparently healthy men: prospective analysis from the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Kooperative Gesundheitsforschung in der Region Augsburg study and experimental data. Clin Chem. 2007 April;53(4):693–701. [PubMed]
6. Leong T, Zylberstein D, Graham I, Lissner L, Ward D, Fogarty J, Bengtsson C, Bjorkelund C, Thelle D. Asymmetric dimethylarginine independently predicts fatal and nonfatal myocardial infarction and stroke in women: 24-year follow-up of the population study of women in Gothenburg. Arterioscler Thromb Vasc Biol. 2008 May;28(5):961–7. [PubMed]
7. Wanby P, Teerlink T, Brudin L, Brattstrom L, Nilsson I, Palmqvist P, Carlsson M. Asymmetric dimethylarginine (ADMA) as a risk marker for stroke and TIA in a Swedish population. Atherosclerosis. 2006 April;185(2):271–7. [PubMed]
8. Meinitzer A, Seelhorst U, Wellnitz B, Halwachs-Baumann G, Boehm BO, Winkelmann BR, Marz W. Asymmetrical dimethylarginine independently predicts total and cardiovascular mortality in individuals with angiographic coronary artery disease (the Ludwigshafen Risk and Cardiovascular Health study) Clin Chem. 2007 February;53(2):273–83. [PubMed]
9. Schnabel R, Blankenberg S, Lubos E, Lackner KJ, Rupprecht HJ, Espinola-Klein C, Jachmann N, Post F, Peetz D, Bickel C, Cambien F, Tiret L, Munzel T. Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study. Circ Res. 2005 September 2;97(5):e53–e59. [PubMed]
10. Nijveldt RJ, Teerlink T, Van Der Hoven B, Siroen MP, Kuik DJ, Rauwerda JA, van Leeuwen PA. Asymmetrical dimethylarginine (ADMA) in critically ill patients: high plasma ADMA concentration is an independent risk factor of ICU mortality. Clin Nutr. 2003 February;22(1):23–30. [PubMed]
11. Zoccali C, Bode-Boger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L, Cataliotti A, Bellanuova I, Fermo I, Frolich J, Boger R. Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet. 2001 December 22;358(9299):2113–7. [PubMed]
12. Kielstein JT, Impraim B, Simmel S, Bode-Boger SM, Tsikas D, Frolich JC, Hoeper MM, Haller H, Fliser D. Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation. 2004 January 20;109(2):172–7. [PubMed]
13. Boger RH, Bode-Boger SM, Szuba A, Tsao PS, Chan JR, Tangphao O, Blaschke TF, Cooke JP. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation. 1998 November 3;98(18):1842–7. [PubMed]
14. Schulze F, Lenzen H, Hanefeld C, Bartling A, Osterziel KJ, Goudeva L, Schmidt-Lucke C, Kusus M, Maas R, Schwedhelm E, Strodter D, Simon BC, Mugge A, Daniel WG, Tillmanns H, Maisch B, Streichert T, Boger RH. Asymmetric dimethylarginine is an independent risk factor for coronary heart disease: results from the multicenter Coronary Artery Risk Determination investigating the Influence of ADMA Concentration (CARDIAC) study. Am Heart J. 2006 September;152(3):493–8. [PubMed]
15. Achan V, Broadhead M, Malaki M, Whitley G, Leiper J, MacAllister R, Vallance P. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol. 2003 August 1;23(8):1455–9. [PubMed]
16. Iribarren C, Husson G, Sydow K, Wang BY, Sidney S, Cooke JP. Asymmetric dimethyl-arginine and coronary artery calcification in young adults entering middle age: the CARDIA Study. Eur J Cardiovasc Prev Rehabil. 2007 April;14(2):222–9. [PubMed]
17. Miyazaki H, Matsuoka H, Cooke JP, Usui M, Ueda S, Okuda S, Imaizumi T. Endogenous nitric oxide synthase inhibitor: a novel marker of atherosclerosis. Circulation. 1999 March 9;99(9):1141–6. [PubMed]
18. Furuki K, Adachi H, Matsuoka H, Enomoto M, Satoh A, Hino A, Hirai Y, Imaizumi T. Plasma levels of asymmetric dimethylarginine (ADMA) are related to intima-media thickness of the carotid artery: an epidemiological study. Atherosclerosis. 2007 March;191(1):206–10. [PubMed]
19. Zoccali C, Benedetto FA, Maas R, Mallamaci F, Tripepi G, Malatino LS, Boger R. Asymmetric dimethylarginine, C-reactive protein, and carotid intima-media thickness in end-stage renal disease. J Am Soc Nephrol. 2002 February;13(2):490–6. [PubMed]
20. Nanayakkara PW, Teerlink T, Stehouwer CD, Allajar D, Spijkerman A, Schalkwijk C, ter Wee PM, van GC. Plasma asymmetric dimethylarginine (ADMA) concentration is independently associated with carotid intima-media thickness and plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) concentration in patients with mild-to-moderate renal failure. Kidney Int. 2005 November;68(5):2230–6. [PubMed]
21. Wanby P, Nilsson I, Brudin L, Nyhammar I, Gustafsson I, Carlsson M. Increased plasma levels of asymmetric dimethylarginine in patients with carotid stenosis: no evidence for the role of the common FABP2 A54T gene polymorphism. Acta Neurol Scand. 2007 February;115(2):90–6. [PubMed]
22. Zsuga J, Torok J, Magyar MT, Valikovics A, Gesztelyi R, Keki S, Csiba L, Zsuga M, Bereczki D. Serum asymmetric dimethylarginine negatively correlates with intima-media thickness in early-onset atherosclerosis. Cerebrovasc Dis. 2007;23(56):388–94. [PubMed]
23. Chirinos JA, David R, Bralley JA, Zea-Diaz H, Munoz-Atahualpa E, Corrales-Medina F, Cuba-Bustinza C, Chirinos-Pacheco J, Medina-Lezama J. Endogenous nitric oxide synthase inhibitors, arterial hemodynamics, and subclinical vascular disease: the PREVENCION Study. Hypertension. 2008 December;52(6):1051–9. [PubMed]
24. Furuki K, Adachi H, Enomoto M, Otsuka M, Fukami A, Kumagae S, Matsuoka H, Nanjo Y, Kakuma T, Imaizumi T. Plasma level of asymmetric dimethylarginine (ADMA) as a predictor of carotid intima-media thickness progression: six-year prospective study using carotid ultrasonography. Hypertens Res. 2008 June;31(6):1185–9. [PubMed]
25. Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA. 1999 December 1;282(21):2035–42. [PubMed]
26. Kannel WB, Feinleib M, McNamara PM, Garrison RJ, Castelli WP. An investigation of coronary heart disease in families. The Framingham offspring study. Am J Epidemiol. 1979 September;110(3):281–90. [PubMed]
27. Fox CS, Cupples LA, Chazaro I, Polak JF, Wolf PA, D'Agostino RB, Ordovas JM, O'Donnell CJ. Genomewide linkage analysis for internal carotid artery intimal medial thickness: evidence for linkage to chromosome 12. Am J Hum Genet. 2004 February;74(2):253–61. [PubMed]
28. O'Leary DH, Polak JF, Kronmal RA, Kittner SJ, Bond MG, Wolfson SK, Jr, Bommer W, Price TR, Gardin JM, Savage PJ. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. The CHS Collaborative Research Group. Stroke. 1992 December;23(12):1752–60. [PubMed]
29. Schwedhelm E, Tan-Andresen J, Maas R, Riederer U, Schulze F, Boger RH. Liquid chromatography-tandem mass spectrometry method for the analysis of asymmetric dimethylarginine in human plasma. Clin Chem. 2005 July;51(7):1268–71. [PubMed]
30. Schwedhelm E, Maas R, Tan-Andresen J, Schulze F, Riederer U, Boger RH. High-throughput liquid chromatographic-tandem mass spectrometric determination of arginine and dimethylated arginine derivatives in human and mouse plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2007 May 15;851(12):211–9. [PubMed]
31. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998 May 12;97(18):1837–47. [PubMed]
32. De CR, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA, Jr, Shin WS, Liao JK. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995 July;96(1):60–8. [PMC free article] [PubMed]
33. Yogo K, Shimokawa H, Funakoshi H, Kandabashi T, Miyata K, Okamoto S, Egashira K, Huang P, Akaike T, Takeshita A. Different vasculoprotective roles of NO synthase isoforms in vascular lesion formation in mice. Arterioscler Thromb Vasc Biol. 2000 November;20(11):E96–E100. [PubMed]
34. Nakata S, Tsutsui M, Shimokawa H, Suda O, Morishita T, Shibata K, Yatera Y, Sabanai K, Tanimoto A, Nagasaki M, Tasaki H, Sasaguri Y, Nakashima Y, Otsuji Y, Yanagihara N. Spontaneous myocardial infarction in mice lacking all nitric oxide synthase isoforms. Circulation. 2008 April 29;117(17):2211–23. [PubMed]
35. Cardounel AJ, Cui H, Samouilov A, Johnson W, Kearns P, Tsai AL, Berka V, Zweier JL. Evidence for the pathophysiological role of endogenous methylarginines in regulation of endothelial NO production and vascular function. J Biol Chem. 2007 January 12;282(2):879–87. [PubMed]
36. Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, O'Hara B, Rossiter S, Anthony S, Madhani M, Selwood D, Smith C, Wojciak-Stothard B, Rudiger A, Stidwill R, McDonald NQ, Vallance P. Disruption of methylarginine metabolism impairs vascular homeostasis. Nat Med. 2007 February;13(2):198–203. [PubMed]
37. Konishi H, Sydow K, Cooke JP. Dimethylarginine dimethylaminohydrolase promotes endothelial repair after vascular injury. J Am Coll Cardiol. 2007 March 13;49(10):1099–105. [PubMed]
38. Hasegawa K, Wakino S, Tatematsu S, Yoshioka K, Homma K, Sugano N, Kimoto M, Hayashi K, Itoh H. Role of asymmetric dimethylarginine in vascular injury in transgenic mice overexpressing dimethylarginie dimethylaminohydrolase 2. Circ Res. 2007 July 20;101(2):e2–10. [PubMed]
39. Maas R. Pharmacotherapies and their influence on asymmetric dimethylargine (ADMA) Vasc Med. 2005 July;10 1:S49–S57. [PubMed]
40. DeBakey ME, Glaeser DH. Patterns of atherosclerosis: effect of risk factors on recurrence and survival-analysis of 11,890 cases with more than 25-year follow-up. Am J Cardiol. 2000 May 1;85(9):1045–53. [PubMed]
41. O'Leary DH, Polak JF, Kronmal RA, Savage PJ, Borhani NO, Kittner SJ, Tracy R, Gardin JM, Price TR, Furberg CD. Thickening of the carotid wall. A marker for atherosclerosis in the elderly? Cardiovascular Health Study Collaborative Research Group. Stroke. 1996 February;27(2):224–31. [PubMed]
42. Schott LL, Wildman RP, Brockwell S, Simkin-Silverman LR, Kuller LH, Sutton-Tyrrell K. Segment-specific effects of cardiovascular risk factors on carotid artery intima-medial thickness in women at midlife. Arterioscler Thromb Vasc Biol. 2004 October;24(10):1951–6. [PubMed]
43. Howard G, Burke GL, Evans GW, Crouse JR, III, Riley W, Arnett D, de LR, Heiss G. Relations of intimal-medial thickness among sites within the carotid artery as evaluated by B-mode ultrasound. ARIC Investigators. Atherosclerosis Risk in Communities. Stroke. 1994 August;25(8):1581–7. [PubMed]
44. Psaty BM, Furberg CD, Kuller LH, Bild DE, Rautaharju PM, Polak JF, Bovill E, Gottdiener JS. Traditional risk factors and subclinical disease measures as predictors of first myocardial infarction in older adults: the Cardiovascular Health Study. Arch Intern Med. 1999 June 28;159(12):1339–47. [PubMed]
45. Mackinnon AD, Jerrard-Dunne P, Sitzer M, Buehler A, von KS, Markus HS. Rates and determinants of site-specific progression of carotid artery intima-media thickness: the carotid atherosclerosis progression study. Stroke. 2004 September;35(9):2150–4. [PubMed]
46. Zarins CK, Giddens DP, Bharadvaj BK, Sottiurai VS, Mabon RF, Glagov S. Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress. Circ Res. 1983 October;53(4):502–14. [PubMed]