Homoarginine:ADMA Ratio in Cardiovascular Health
Clinical Significance
The homoarginine:ADMA ratio serves as an independent predictor of cardiovascular mortality and events, with lower ratios consistently associated with worse outcomes across multiple cardiovascular disease populations. 1
Mechanistic Foundation
The ratio's predictive value stems from opposing effects on nitric oxide (NO) bioavailability:
- ADMA acts as a competitive inhibitor of all three nitric oxide synthase (NOS) isoforms, directly competing with L-arginine at the enzyme's active site, thereby reducing NO production and impairing endothelial function 2
- Homoarginine may counteract the proatherogenic effects of ADMA, though the exact mechanisms remain under investigation 1
- Homocysteine metabolism worsens this balance by activating arginine-protein-methyltransferases (which convert L-arginine to ADMA) while simultaneously downregulating dimethylarginine-dimethylaminohydrolase (DDAH), the enzyme responsible for ADMA degradation 2
Evidence for Prognostic Value
Lower Extremity Arterial Disease
- Low homoarginine/ADMA ratio independently predicts cardiovascular mortality (HR 2.803,95% CI 1.178-6.674, p=0.020) in claudicant patients over 7.7 years of follow-up 1
- Low homoarginine/ADMA ratio independently predicts cardiovascular events (HR 1.938,95% CI 1.015-3.700, p=0.045) in the same population 1
Venous Thromboembolism
- Low homoarginine and high ADMA independently predict all-cause mortality in patients with suspected VTE after adjustment for multiple cardiovascular risk factors, cancer, and renal function 3
- These parameters appear to serve as markers of "frailty" rather than predictors of VTE recurrence specifically 3
Community-Based Populations
- Higher homoarginine levels associate with lower mortality risk (HR per SD increment 0.83,95% CI 0.74-0.93) in the Framingham Offspring Study over 18 years of follow-up 4
- Participants with higher homoarginine and lower ADMA demonstrate the lowest mortality risk (HR 0.81,95% CI 0.67-0.98) compared to those with low levels of both 4
Diastolic Dysfunction
- Lower homoarginine levels associate with presence of diastolic dysfunction, while higher ADMA and SDMA levels correlate with severity of diastolic dysfunction in patients with preserved ejection fraction 5
- All three markers correlate with NT-proBNP and midregional pro-adrenomedullin after adjustment for cardiovascular risk factors 5
Reference Intervals for Risk Stratification
Normal serum concentrations in healthy individuals (Study of Health in Pomerania):
- Homoarginine: 1.41-5.00 μmol/L (men), 1.20-5.53 μmol/L (women) 6
- ADMA: 0.41-0.95 μmol/L (men), 0.43-0.96 μmol/L (women) 6
- Median homoarginine: 2.63 μmol/L; median ADMA: 0.64 μmol/L 6
Clinical Application Algorithm
For cardiovascular risk stratification:
- Measure both homoarginine and ADMA (preferably by LC-MS/MS) 3, 1
- Calculate the homoarginine:ADMA ratio 1
- Stratify risk based on ratio quartiles, with lower quartile indicating highest risk for cardiovascular mortality and events 1
- Consider ratio alongside traditional cardiovascular risk factors for comprehensive risk assessment 4, 5
Critical Caveats
Therapeutic Limitations
- Folate-mediated homocysteine lowering does not reduce ADMA levels and may paradoxically increase ADMA production by augmenting the methionine pool, resulting in enhanced protein methyltransferase-mediated conversion of L-arginine to ADMA 2
- Arginine supplementation carries theoretical risks, including increased availability of proproliferative polyamines that may promote vascular smooth muscle proliferation and atherosclerotic plaque progression 2