European Heart Journal Advance Access originally published online on August 6, 2008
European Heart Journal 2008 29(20):2506-2513; doi:10.1093/eurheartj/ehn360
Differential effects of arginine methylation on diastolic dysfunction and disease progression in patients with chronic systolic heart failure
1 Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, F25, Cleveland, OH 44195, USA
2 Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
3 Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA
4 Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand
Received 25 February 2008; revised 15 July 2008; accepted 17 July 2008; online publish-ahead-of-print 6 August 2008.
* Corresponding author. Tel: +1 216 444 2121, Fax: +1 216 445 6165, Email: tangw{at}ccf.org
See page 2453 for the editorial comment on this article (doi:10.1093/eurheartj/ehn393)
Aims: To investigate the association of arginine methylation with myocardial function and prognosis in chronic systolic heart failure patients.
Methods and 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).
Conclusion: 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.
Key Words: Heart failure • Arginine • Methylation • Diastolic function • Prognosis
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