Association of plasma ADMA levels with MRI markers of vascular brain injury: Framingham offspring study.
OBJECTIVE
Asymmetrical dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, is a marker of endothelial dysfunction. Elevated circulating ADMA concentrations have been associated with systemic and carotid atherosclerosis, an elevated risk of developing stroke, and magnetic resonance imaging white-matter hyperintensities (WMHs). The relation of plasma ADMA to subclinical vascular brain injury has not been previously studied in a middle-aged, community-based sample.


METHODS
In 2013 stroke-free Framingham offspring (mean+/-SD age, 58+/-9.5 years; 53% women), we related baseline plasma ADMA levels (1995-1998) to subsequent brain magnetic resonance imaging measures (1999-2004) of subclinical vascular injury: presence of silent brain infarcts (SBIs) and large white-matter hyperintensity volumes (LWMHs; defined as >1 SD above the age-specific mean).


RESULTS
Prevalences of SBIs and LWMHs were 10.7% and 12.6%, respectively. In multivariable analyses adjusting for age, sex and traditional stroke risk factors, higher ADMA levels were associated with an increased risk of prevalent SBIs (odds ratio [OR] per 1-SD increase in ADMA=1.16; 95% CI, 1.01 to 1.33; P=0.04). We observed that participants in the upper 3 age-specific quartiles (Qs) of plasma ADMA values had an increased prevalence of SBIs (OR for Q2-Q4 vs Q1=1.43; 95% CI, 1.00 to 2.04; P<0.05). The prevalence of SBIs in Q1and Q2-Q4 was 8.3% and 11.6%, respectively. The prevalence of LWMHs did not differ according to ADMA concentrations.


CONCLUSIONS
Higher plasma ADMA values were associated with an increased prevalence of SBIs, after adjustment for traditional stroke risk factors. Thus, ADMA may be a potentially useful new biomarker of subclinical vascular brain injury, which is an important correlate of vascular cognitive impairment and risk of stroke.
Pikula
Aleksandra
A
Boston University School of Medicine, Boston, MA, USA.
Böger
Rainer H
RH
Beiser
Alexa S
AS
Maas
Renke
R
DeCarli
Charles
C
Schwedhelm
Edzard
E
Himali
Jayandra J
JJ
Schulze
Friedrich
F
Au
Rhoda
R
Kelly-Hayes
Margaret
M
Kase
Carlos S
CS
Vasan
Ramachandran S
RS
Wolf
Philip A
PA
Seshadri
Sudha
S
D000328:Adult; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D050197:Atherosclerosis / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000000981:diagnostic imaging*; D020520:Brain Infarction / Q000097:blood* / Q000000981:diagnostic imaging*; D015331:Cohort Studies; D004730:Endothelium, Vascular / Q000201:enzymology; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D011859:Radiography; D012307:Risk Factors
D015415:Biomarkers; C018524:N,N-dimethylarginine; D001120:Arginine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III