Asymmetric dimethylarginine and cardiovascular risk: systematic review and meta-analysis of 22 prospective studies

Abstract

Background: Asymmetric dimethylarginine (ADMA) inhibits the production of nitric oxide, a key regulator of the vascular tone, and may be important in the development of cardiovascular disease (CVD). Our aim was to reliably quantify the association of ADMA and its isomer symmetric dimethylarginine (SDMA) with the risk of CVD outcomes in long-term cohort studies.

Methods and results: Data were collated from 22 prospective studies involving a total of 19 842 participants, which have recorded 2339 CVD, 997 coronary heart disease, and 467 stroke outcomes during a mean follow-up of 7.1 years. In a comparison of individuals in the top with those in the bottom third of baseline ADMA values, the combined risk ratios were 1.42 (95% confidence interval: 1.29 to 1.56) for CVD, 1.39 for coronary heart disease (1.19 to 1.62), and 1.60 for stroke (1.33 to 1.91). Broadly similar results were observed according to participants' baseline disease status (risk ratios for CVD: 1.35 [1.18 to 1.54] in general populations; 1.47 [1.16 to 1.87] in individuals with pre-existing CVD; and 1.52 [1.26 to 1.84] in individuals with pre-existing kidney disease) and by different study characteristics, including geographical location, sample type, assay method, number of incident outcomes, and level of statistical adjustment (all P values>0.05). In contrast, in 8 prospective studies involving 9070 participants and 848 outcomes, the corresponding estimate for SDMA concentration was 1.32 (0.92 to 1.90) for CVD.

Conclusions: Available prospective studies suggest associations between circulating ADMA concentration and CVD outcomes under a broad range of circumstances. Further research is needed to better clarify these associations, particularly in large general population studies.

Keywords: asymmetric dimethylarginine; cardiovascular diseases; meta‐analysis; prospective studies.

Figure 1

Study flow diagram. ADMA indicates asymmetric dimethylarginine; CVD, cardiovascular disease; SDMA, symmetric dimethylarginine.

Figure 2

Combined RRs (95% CI) for cardiovascular outcomes in individuals in the top compared with those in the bottom third of ADMA and SDMA concentration. When analysis was restricted to studies that reported on both methylarginines (for direct comparison), the RR of ADMA was 1.40 (1.16, 1.68) for CVD, 1.24 (1.01, 1.52) for CHD, and 1.57 (1.12, 2.20) for stroke and the RR of SDMA was 1.32 (0.92, 1.90) for CVD, 1.44 (0.77, 2.67) for CHD, and 1.31 (0.83, 2.07) for stroke. ADMA indicates asymmetric dimethylarginine; CHD, coronary heart disease; CVD, cardiovascular disease; RR, risk ratio; SDMA, symmetric dimethylarginine.

Figure 3

Reported RRs (95% CI) for cardiovascular outcomes in individuals in the top compared with those in the bottom third of ADMA concentration. I² (95% CI) was 16% (0%, 53%) for CVD, 14% (0%, 55%) for CHD and 0% (0%, 71%) for stroke. ADMA indicates asymmetric dimethylarginine; ALERT, Assessment of Lescol in Renal Transplantation Study; BECAC, Bergen coronary angiography cohort; BRUNECK, Bruneck Study; CHD, coronary heart disease; CREED, Cardiovascular Risk Extended Evaluation in Dialysis; CVD, cardiovascular disease; DHS, Dallas Heart Study; GetABI, German Epidemiological Trial on Ankle Brachial Index; INCHIANTI, Invecchiare in Chianti Study; KAROLA, Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung; KIHD, Kuopio Ischaemic Heart Disease Study; KVINNOSTUDIEN, Kvinnostudien Population Study of Women in Gothenburg; MDC, Malmö Diet and Cancer Cardiovascular Cohort; MDRD, Modification of Diet in Renal Disease Study; MONICA/KORA, Monitoring of Trends and Determinants in Cardiovascular Disease Augsburg; PAD, peripheral arterial disease; RRs, risk ratios; SDC, Steno Diabetes Center.

Figure 4

Association of ADMA concentration with CVD risk according to different clinically relevant characteristics. + indicates adjusted for age and sex; ++, further adjusted for at least 2 conventional CVD risk factors; +++, additionally adjusted for other factors; ADMA, asymmetric dimethylarginine; CVD, cardiovascular disease; ELISA, enzyme-linked immunosorbent assay; GP, general practitioner; HPLC, high-performance liquid chromatography; LC-MS/MS, liquid chromatography with tandem mass spectrometry; o, unadjusted; RR, risk ratio.

Figure 5

Funnel plots of reported associations between ADMA and cardiovascular outcomes. The dotted lines show pseudo 95% confidence intervals around the overall pooled estimate. P values are from Egger’s asymmetry test of associations. ADMA indicates asymmetric dimethylarginine; ALERT, Assessment of Lescol in Renal Transplantation Study; BECAC, Bergen coronary angiography cohort; BRUNECK, Bruneck Study; CHD, coronary heart disease; CREED, Cardiovascular Risk Extended Evaluation in Dialysis; CVD, cardiovascular disease; DHS, Dallas Heart Study; GetABI, German Epidemiological Trial on Ankle Brachial Index; KAROLA, Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung; KVINNOSTUDIEN, Kvinnostudien Population Study of Women in Gothenburg; MDC, Malmö Diet and Cancer Cardiovascular Cohort; MDRD, Modification of Diet in Renal Disease Study; MONICA/KORA, Monitoring of Trends and Determinants in Cardiovascular Disease Augsburg; PAD, peripheral arterial disease; RR, risk ratio; SDC, Steno Diabetes Center.

Figure 6

Reported RRs (95% CI) for cardiovascular outcomes in individuals in the top compared with those in the bottom third of SDMA concentration. I² (95% CI) was 69% (36%, 85%) for CVD, 77% (37%, 92%) for CHD and 27% (0%, 92%) for stroke. BRUNECK indicates Bruneck Study; CHD, coronary heart disease; CVD, cardiovascular disease; DHS, Dallas Heart Study; GetABI, German Epidemiological Trial on Ankle Brachial Index; KAROLA, Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung; PAD, peripheral arterial disease; RRs, risk ratios; SDMA, symmetric dimethylarginine.