Abstract Body (Do not enter title and authors here): Introduction: As substrates for nitric oxide, arginine (Arg) and its metabolites are involved in the regulation of vascular function. Ischemia caused by vascular dysfunction is common in patients with non-obstructive coronary artery disease (NOCAD) and may indicate a subgroup at increased risk of cardiovascular disease (CVD) mortality.
Research question: We evaluated serum arginine (Arg), homoarginine (hArg), symmetric dimethylarginine (SDMA), and asymmetric dimethyl arginine (ADMA) as long-term predictors of CVD mortality in patients with chronic coronary syndrom. Particularly, we were interested in potential effect modifications according to diagnoses of NOCAD versus obstructive coronary artery disease (OCAD) at baseline invasive coronary angiography (ICA).
Methods: 4164 patients underwent elective ICA from 2000-2004. Serum metabolite concentrations were measured by liquid chromatography-tandem mass spectrometry using isotope labelled internal standards. Metabolite associations with CVD mortality risk were explored by Cox regression adjusting for age, sex, body mass index, HbA1c, hypertension, smoking status, serum LDL cholesterol, previous myocardial infarction, and estimated glomerular filtration rate. HRs (95% CI) are reported per SD increment of (log transformed) metabolites. Potential effect modifiers were evaluated by adding interaction terms to the model.
Results: Median age was 62 years at inclusion. 72 % were men, 25 % had NOCAD, while 75 % had OCAD. During median 14 years of follow-up, 14 % of patients died from CVD. In multivariable analyses, serum concentrations of Arg, hArg and SDMA predicted CVD mortality with HRs (95% CI) of 0.90 (0.83-0.98), 0.81 (0.74-0.88) and 1.30 (1.12-1.50), respectively. Serum hArg was a significantly stronger inverse predictor in patients with NOCAD than in OCAD with HR (95% CI) of 0.54 (0.40-0.73) versus 0.84 (0.77-0.92), respectively (Pint = 0.037). No significant effect modifications were observed for the other arginine form (Pint ≥ 0.09).
Conclusion: In patients with stable chest pain, Arg, hArg and SDMA significantly predicted long term CVD mortality. Interestingly, hArg was a stronger inverse predictor among NOCAD compared to OCAD patients. Further studies investigating hArg as a potential marker of a high-risk phenotype in NOCAD are merited.