Differential effects of arginine methylation on diastolic dysfunction and disease progression in patients with chronic systolic heart failure

Abstract

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.

Figures

Figure 1

Scheme of arginine metabolic pathways in high throughput mass spectrometry arrays. NOS, nitric oxide synthase isoforms; ADMA, asymmetric dimethylarginine; SDMA, symmetric dimethylarginine; MMA, N-mono-methylarginine; DDAH, dimethylarginine dimethylaminohydrolase; PRMT, protein arginine methyltransferases; CAT, cationic amino acid transport.

Figure 2

Relation of plasma levels of methylated arginine metabolites and mitral E/tissue Doppler septal Ea (E/E′). [(A) ADMA; (B) SDMA; (C) MMA; (D) Methyl-lysine].

Figure 3

Relation of plasma levels of methylated arginine metabolites and plasma levels of NT-proBNP [(A) ADMA; (B) SDMA; (C) MMA; (D) Methyl-lysine].

Figure 4

Kaplan–Meier analysis of event-free survival stratified according to plasma levels of ADMA (A) and SDMA (B).