For personal use. Only reproduce with permission from The Lancet Publishing Group. RESEARCH LETTERS Asymmetrical dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor, which has been suggested to be a novel independent risk factor for endothelial dysfunction and coronary heart disease. We investigated the association of ADMA concentration in serum with risk of acute coronary events. We did a prospective, nested, case-control study in middle-aged men from eastern Finland. In an analysis of men who did not smoke, those who were in the highest quartile for ADMA (>0·62 μmol/L) had a 3·9-fold (95% CI 1·25–12·3, p=0·02) increase in risk of acute coronary events compared with the other quartiles. Our findings suggest that ADMA is a predictor of acute coronary events. Lancet 2001; 358: 2127–28 See Commentary page 2096 Nitrovasodilator drugs have played an essential part in coronary care throughout the past century; however, the role of endothelium in vascular functions was unknown until identification of nitric oxide. In the past decade, the link between endothelium and atherogenesis has been made. Endothelium has an important role in monocyte and leucocyte adhesion, platelet aggregation, thrombosis, smooth-muscle cell proliferation, and vasoregulation. Furthermore, reduced bioavailability of nitric oxide has been implicated in the pathogenesis of hypertension, atherosclerosis, and diabetes. In the early 1990s, Vallance and coworkers 1 characterised asymmetrical dimethylarginine (ADMA) as an endogenous inhibitor of nitric oxide synthase. In young hypercholesterolaemic individuals, increase of ADMA concentration was associated with impaired endothelium- dependent vasodilation. 2 Also, coronary endothelial dysfunction predicts long-term atherosclerotic-disease progression and cardiovascular-event rates. 3 Our aim was to assess the hypothesis that high concentration in serum of ADMA, an indicator of endothelial dysfunction, is associated with a raised risk of acute coronary events in middle-aged men. We focused on high ADMA concentrations (highest quartile) because we postulated that there would be a raised risk only at high concentrations of ADMA, which could lead to deterioration of endothelial function. The study population was taken from a sample of 1038 men aged 46, 52, 58, and 64 years who were examined in the Kuopio Ischaemic Heart Disease Risk Factor Study between 1991 and 1993. 71 men who had their first acute coronary event by the end of 1997 were included in the study. Two controls were matched for every case by age, examination day and month, coronary-heart-disease history, and residence (from the same municipality). We excluded three controls because of an insufficient blood sample; thus, 139 controls were included in the study. Of these men, 150 were non- smokers (45 cases, 105 controls) and 60 were smokers (26 cases, 34 controls). Acute coronary events that occurred by the end of 1992 were registered by the MONICA (MONItoring of trends and determinants in CArdiovascular disease) THE LANCET • Vol 358 • December 22/29, 2001 2127 Research letters Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine Veli-Pekka Valkonen, Hannu Päivä, Jukka T Salonen, Timo A Lakka, Terho Lehtimäki, Juha Laakso, Reijo Laaksonen All (n=150) No CHD history CHD history (n=70) Difference between groups p (n=80) Mean difference 95% CI Clinical Age (years, matched) 59·9 (5·5) 58·0 (6·1) 61·9 (3·9) 3·9 2·3 to 5·6 <0·0001 Body-mass-index (kg/m 2 ) 28·2 (3·6) 27·8 (3·5) 28·6 (3·8) 0·8 –0·4 to 1·9 0·210 Systolic blood pressure (mm Hg) 138 (16) 138 (17) 134 (16) 1·1 –4·3 to 6·4 0·697 Diastolic blood pressure (mm Hg) 88 (10) 89 (11) 87 (8) –2·1 –5·2 to 1·1 0·188 Hypertension 65·3% 47·5% 85·7% 38·2% 24·3 to 52·1 <0·0001 Diabetes 8·7% 6·3% 11·4% 5·2% –4·1 to 14·5 0·273 Biochemical Serum ADMA (mol/L) 0·51 (0·16) 0·51 (0·17) 0·50 (0·14) –0·016 –0·07 to 0·04 0·541 Serum SDMA (mol/L) 0·39 (0·12) 0·39 (0·09) 0·40 (0·15) 0·017 –0·02 to 0·06 0·410 ADMA/SDMA ratio 1·38 (0·60) 1·41 (0·63) 1·34 (0·58) –0·069 –0·26 to 0·13 0·487 Serum L–arginine (mol/L) 140 (29) 140 (29) 141·3 (29) 1·8 –7·6 to 11·2 0·712 Serum HDL cholesterol (mmol/L) 1·03 (0·24) 1·04 (0·24) 1·0 (0·25) –0·03 –0·11 to 0·04 0·382 Serum LDL cholesterol (mmol/L) 3·9 (0·8) 3·84 (0·64) 3·9 (1·0) 0·08 –0·20 to 0·35 0·584 Serum triglycerides (mmol/L) 1·8 (1·1) 1·67 (1·16) 1·95 (1·1) 0·3 –0·08 to 0·64 0·120 Serum apolipoprotein B (mg/L) 998 (265) 965 (252) 1037 (276) 0·07 –0·01 to 0·16 0·098 Blood glucose (mmol/L) 5·4 (1·8) 5·36 (2·1) 5·5 (1·4) 0·1 –0·48 to 0·67 0·738 Serum insulin (mmol/L) 8·9 (5·5) 7·8 (4·7) 10·2 (6·0) 2·5 0·72 to 4·23 0·006 Serum ferritin (g/L) 134 (113) 137 (114) 132 (113) –18·5 –42·0 to 31·2 0·770 Data are mean (SD) unless otherwise shown. ADMA=asymmetrical dimethylarginine; SDMA=symmetrical dimethylarginine; CHD=coronary heart disease. Table 1: Distributions of ADMA, SDMA, L-arginine, and other risk factors analysed among non-smoking men