Differential effects of arginine methylation on diastolic dysfunction and disease progression in patients with chronic systolic heart failure.
OBJECTIVE
To investigate the association of arginine methylation with myocardial function and prognosis in chronic systolic heart failure patients.


RESULTS
Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), as well as N-mono-methylarginine (MMA) and methyl-lysine, were simultaneously measured by tandem mass spectrometry in 132 patients with chronic systolic heart failure with echocardiographic evaluation and follow-up. Increasing ADMA and SDMA levels were associated with elevated natriuretic peptide levels (both P < 0.001), and increasing SDMA levels were associated with worsening renal function (P < 0.001). Higher plasma levels of methylated arginine metabolites (but not methyl-lysine) were associated with the presence of left ventricular (LV) diastolic dysfunction (E/septal E', Spearman's r = 0.31-0.36, P < 0.001). Patients taking beta-blockers had lower ADMA levels than those not taking beta-blockers [0.42 (0.33, 0.50) vs. 0.51 (0.40, 0.58), P < 0.001]. Only increasing ADMA levels were associated with advanced right ventricular (RV) systolic dysfunction. Elevated ADMA levels remained a consistent independent predictor of adverse clinical events (hazard ratio = 1.64, 95% CI: 1.20-2.22, P = 0.002).


CONCLUSIONS
In chronic systolic heart failure, accumulation of methylated arginine metabolites is associated with the presence of LV diastolic dysfunction. Among the methylated derivatives of arginine, ADMA provides the strongest independent prediction of disease progression and adverse long-term outcomes.
Tang
Wai Hong Wilson
WH
Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. tangw@ccf.org
Tong
Wilson
W
Shrestha
Kevin
K
Wang
Zeneng
Z
Levison
Bruce S
BS
Delfraino
Brian
B
Hu
Bo
B
Troughton
Richard W
RW
Klein
Allan L
AL
Hazen
Stanley L
SL
D001120:Arginine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002908:Chronic Disease; D003971:Diastole / Q000187:drug effects; D018450:Disease Progression; D015150:Echocardiography, Doppler; D004562:Electrocardiography; D005260:Female; D054143:Heart Failure, Systolic / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D045265:Natriuretic Peptides / Q000378:metabolism* / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis; D011237:Predictive Value of Tests; D011446:Prospective Studies; D051437:Renal Insufficiency / Q000139:chemically induced; D053719:Tandem Mass Spectrometry / Q000379:methods; D016896:Treatment Outcome; D020257:Ventricular Remodeling / Q000502:physiology
D015415:Biomarkers; D045265:Natriuretic Peptides; D009569:Nitric Oxide; C024917:symmetric dimethylarginine; D001120:Arginine