Increased levels of Symmetric dimethyl-arginine are associated with all-cause mortality in patients with symptomatic peripheral arterial disease

Aleksandra Staniszewska , Sriram Rajagopalan, Abdullah Al-Shaheen, Frank Thies, Julie Brittenden (Corresponding Author)

Research output: Contribution to journalArticle

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Abstract

OBJECTIVE: Recent interest has focused on the role of the methyl-arginines, endogenous inhibitors of nitric oxide, as adverse prognostic indicators. To date, few studies have assessed the role of symmetric dimethyl-arginine (SDMA) in patients with peripheral arterial disease. We aimed to determine the relationship, if any, of SDMA to all-cause mortality and disease severity as assessed by the ankle-brachial index (ABI) in patients with symptomatic peripheral arterial disease (PAD).

METHODS: In 238 patients with symptomatic PAD and an ABI of <0.8, l-arginine, asymmetric dimethyl-arginine (ADMA) and SDMA levels were measured by hydrophilic-interaction liquid chromatography-electrospray tandem mass spectrometry.

RESULTS: The median follow-up was 6 years 11 months (interquartile range [IQR], 4 years 5 months-7 years 10 months). SDMA and ADMA levels were higher in those who died compared with those who survived (0.51 [IQR, 0.44-0.66] μmol/L vs 0.46 [IQR, 0.39-0.55] μmol/L, P ≤ .001; and 0.48 [IQR, 0.41-0.55] μmol/L vs 0.45 [IQR, 0.39-0.50] μmol/L, P = .007, respectively). l-arginine levels were similar in the two groups. On multivariate analysis, SDMA and ADMA as continuous variable were significantly associated with mortality (P = .001). For SDMA and ADMA, the highest compared with the lowest quartile levels were significantly associated with mortality (SDMA: hazard ratio, 3.855; 95% confidence interval, 1.625-9.143; P = .002; ADMA: hazard ratio, 2.277; 95% confidence interval, 1.114-4.654; P = .024). ADMA and SDMA showed a negative correlation with severity of PAD as assessed by ABI (r = -0.236, N = 216, P < .001; r = -0.209, N = 208, P = .002, respectively).

CONCLUSIONS: The novel finding of this study is that SDMA levels were predictive of all cause-mortality and correlated with disease severity. Further studies should assess the role of nitric oxide donors in patients with high levels of SDMA.

Original languageEnglish
Pages (from-to)1292-1298
Number of pages7
JournalJournal of Vascular Surgery
Volume61
Issue number5
Early online date13 Mar 2015
DOIs
Publication statusPublished - May 2015

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Peripheral Arterial Disease
Arginine
Mortality
Ankle Brachial Index
Confidence Intervals
Nitric Oxide Donors

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Increased levels of Symmetric dimethyl-arginine are associated with all-cause mortality in patients with symptomatic peripheral arterial disease. / Staniszewska , Aleksandra; Rajagopalan, Sriram; Al-Shaheen, Abdullah ; Thies, Frank; Brittenden, Julie (Corresponding Author).

In: Journal of Vascular Surgery, Vol. 61, No. 5, 05.2015, p. 1292-1298.

Research output: Contribution to journalArticle

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title = "Increased levels of Symmetric dimethyl-arginine are associated with all-cause mortality in patients with symptomatic peripheral arterial disease",
abstract = "OBJECTIVE: Recent interest has focused on the role of the methyl-arginines, endogenous inhibitors of nitric oxide, as adverse prognostic indicators. To date, few studies have assessed the role of symmetric dimethyl-arginine (SDMA) in patients with peripheral arterial disease. We aimed to determine the relationship, if any, of SDMA to all-cause mortality and disease severity as assessed by the ankle-brachial index (ABI) in patients with symptomatic peripheral arterial disease (PAD).METHODS: In 238 patients with symptomatic PAD and an ABI of <0.8, l-arginine, asymmetric dimethyl-arginine (ADMA) and SDMA levels were measured by hydrophilic-interaction liquid chromatography-electrospray tandem mass spectrometry.RESULTS: The median follow-up was 6 years 11 months (interquartile range [IQR], 4 years 5 months-7 years 10 months). SDMA and ADMA levels were higher in those who died compared with those who survived (0.51 [IQR, 0.44-0.66] μmol/L vs 0.46 [IQR, 0.39-0.55] μmol/L, P ≤ .001; and 0.48 [IQR, 0.41-0.55] μmol/L vs 0.45 [IQR, 0.39-0.50] μmol/L, P = .007, respectively). l-arginine levels were similar in the two groups. On multivariate analysis, SDMA and ADMA as continuous variable were significantly associated with mortality (P = .001). For SDMA and ADMA, the highest compared with the lowest quartile levels were significantly associated with mortality (SDMA: hazard ratio, 3.855; 95{\%} confidence interval, 1.625-9.143; P = .002; ADMA: hazard ratio, 2.277; 95{\%} confidence interval, 1.114-4.654; P = .024). ADMA and SDMA showed a negative correlation with severity of PAD as assessed by ABI (r = -0.236, N = 216, P < .001; r = -0.209, N = 208, P = .002, respectively).CONCLUSIONS: The novel finding of this study is that SDMA levels were predictive of all cause-mortality and correlated with disease severity. Further studies should assess the role of nitric oxide donors in patients with high levels of SDMA.",
author = "Aleksandra Staniszewska and Sriram Rajagopalan and Abdullah Al-Shaheen and Frank Thies and Julie Brittenden",
note = "Copyright {\circledC} 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved. S.R. was sponsored by a grant from the Scottish Chief Scientist Office. A.S. was supported by an Undergraduate Vacation Scholarship from Medical Research Scotland (Vac-697-2013).",
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T1 - Increased levels of Symmetric dimethyl-arginine are associated with all-cause mortality in patients with symptomatic peripheral arterial disease

AU - Staniszewska , Aleksandra

AU - Rajagopalan, Sriram

AU - Al-Shaheen, Abdullah

AU - Thies, Frank

AU - Brittenden, Julie

N1 - Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved. S.R. was sponsored by a grant from the Scottish Chief Scientist Office. A.S. was supported by an Undergraduate Vacation Scholarship from Medical Research Scotland (Vac-697-2013).

PY - 2015/5

Y1 - 2015/5

N2 - OBJECTIVE: Recent interest has focused on the role of the methyl-arginines, endogenous inhibitors of nitric oxide, as adverse prognostic indicators. To date, few studies have assessed the role of symmetric dimethyl-arginine (SDMA) in patients with peripheral arterial disease. We aimed to determine the relationship, if any, of SDMA to all-cause mortality and disease severity as assessed by the ankle-brachial index (ABI) in patients with symptomatic peripheral arterial disease (PAD).METHODS: In 238 patients with symptomatic PAD and an ABI of <0.8, l-arginine, asymmetric dimethyl-arginine (ADMA) and SDMA levels were measured by hydrophilic-interaction liquid chromatography-electrospray tandem mass spectrometry.RESULTS: The median follow-up was 6 years 11 months (interquartile range [IQR], 4 years 5 months-7 years 10 months). SDMA and ADMA levels were higher in those who died compared with those who survived (0.51 [IQR, 0.44-0.66] μmol/L vs 0.46 [IQR, 0.39-0.55] μmol/L, P ≤ .001; and 0.48 [IQR, 0.41-0.55] μmol/L vs 0.45 [IQR, 0.39-0.50] μmol/L, P = .007, respectively). l-arginine levels were similar in the two groups. On multivariate analysis, SDMA and ADMA as continuous variable were significantly associated with mortality (P = .001). For SDMA and ADMA, the highest compared with the lowest quartile levels were significantly associated with mortality (SDMA: hazard ratio, 3.855; 95% confidence interval, 1.625-9.143; P = .002; ADMA: hazard ratio, 2.277; 95% confidence interval, 1.114-4.654; P = .024). ADMA and SDMA showed a negative correlation with severity of PAD as assessed by ABI (r = -0.236, N = 216, P < .001; r = -0.209, N = 208, P = .002, respectively).CONCLUSIONS: The novel finding of this study is that SDMA levels were predictive of all cause-mortality and correlated with disease severity. Further studies should assess the role of nitric oxide donors in patients with high levels of SDMA.

AB - OBJECTIVE: Recent interest has focused on the role of the methyl-arginines, endogenous inhibitors of nitric oxide, as adverse prognostic indicators. To date, few studies have assessed the role of symmetric dimethyl-arginine (SDMA) in patients with peripheral arterial disease. We aimed to determine the relationship, if any, of SDMA to all-cause mortality and disease severity as assessed by the ankle-brachial index (ABI) in patients with symptomatic peripheral arterial disease (PAD).METHODS: In 238 patients with symptomatic PAD and an ABI of <0.8, l-arginine, asymmetric dimethyl-arginine (ADMA) and SDMA levels were measured by hydrophilic-interaction liquid chromatography-electrospray tandem mass spectrometry.RESULTS: The median follow-up was 6 years 11 months (interquartile range [IQR], 4 years 5 months-7 years 10 months). SDMA and ADMA levels were higher in those who died compared with those who survived (0.51 [IQR, 0.44-0.66] μmol/L vs 0.46 [IQR, 0.39-0.55] μmol/L, P ≤ .001; and 0.48 [IQR, 0.41-0.55] μmol/L vs 0.45 [IQR, 0.39-0.50] μmol/L, P = .007, respectively). l-arginine levels were similar in the two groups. On multivariate analysis, SDMA and ADMA as continuous variable were significantly associated with mortality (P = .001). For SDMA and ADMA, the highest compared with the lowest quartile levels were significantly associated with mortality (SDMA: hazard ratio, 3.855; 95% confidence interval, 1.625-9.143; P = .002; ADMA: hazard ratio, 2.277; 95% confidence interval, 1.114-4.654; P = .024). ADMA and SDMA showed a negative correlation with severity of PAD as assessed by ABI (r = -0.236, N = 216, P < .001; r = -0.209, N = 208, P = .002, respectively).CONCLUSIONS: The novel finding of this study is that SDMA levels were predictive of all cause-mortality and correlated with disease severity. Further studies should assess the role of nitric oxide donors in patients with high levels of SDMA.

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DO - 10.1016/j.jvs.2015.01.002

M3 - Article

C2 - 25776186

VL - 61

SP - 1292

EP - 1298

JO - Journal of Vascular Surgery

JF - Journal of Vascular Surgery

SN - 0741-5214

IS - 5

ER -